Abdominal relapse in stage 1 nonseminomatous germ cell tumours of the testis managed by surveillance or with adjuvant chemotherapy.

OBJECTIVE: To assess the impact on patterns of recurrence of adjuvant chemotherapy in patients with stage 1 nonseminomatous germ cell tumours (NSGCT) of the testis, who have a high likelihood of relapse on surveillance if certain risk factors are identified in the orchidectomy specimen, and thus the theoretical need for retroperitoneal lymph node dissection (RPLND). PATIENTS AND METHODS: The incidence of abdominal relapse was recorded in 417 men presenting with stage 1 NSGCT over the past 18 years. Up to 1986, 161 men were managed by surveillance alone, and abdominal relapse occurred in 26. From 1986 onwards, men with positive risk factors in the orchidectomy specimen were offered two courses of chemotherapy; 60 accepted and one relapsed in the abdomen, and 196 underwent surveillance and 19 relapsed in the abdomen. RESULTS: Abdominal relapse was significantly reduced from 16% before 1986 to 8% afterward (P = 0.014). Mortality from testicular tumour or treatment toxicity remained low, at 0.6% before 1986 and 2.0% since then. CONCLUSION: The need for RPLND in stage 1 NSGCT remains highly doubtful.

Para-aortic lymphadenectomy after chemotherapy for metastatic non-seminomatous germ cell tumours: prognostic value and therapeutic benefit.

Between 1976 and 1990, 231 patients had excision of para-aortic lymph node masses remaining after chemotherapy for metastatic non-seminomatous germ cell tumours. The overall 5-year survival rate was 80%. Multivariate analysis of survival after surgery was performed and the following were found to be independent prognostic variables: completeness of surgical excision, pathology of excised mass, timing of surgery after chemotherapy (elective versus salvage) and year of treatment (before or after 1984). Para-aortic lymphadenectomy provided both therapeutic benefit and histological information of prognostic value in planning future treatment and follow-up. Size of mass and serum markers at the time of surgery were of no additional prognostic value once completeness of excision and pathology were taken into account. We therefore recommend that all residual masses should be removed soon after completion of chemotherapy.

Combination chemotherapy with bleomycin, etoposide and cisplatin (BEP) for metastatic testicular teratoma: long-term follow-up.

127 men with previously untreated non-seminomatous germ cell tumours (NSGCT) of the testis were given BEP chemotherapy (bleomycin, etoposide and cisplatin) between 1979-1986. Long-term follow-up (median 65 months) has shown an overall 5 year survival of 87.2% (95% confidence limits 81.1%-93.3%). Outcome was related to both tumour volume and serum marker levels of alpha-fetoprotein (alpha FP) and beta human chorionic gonadotropin (HCG), with 5 year actuarial survivals of 97.8%, 72.2% and 26.7% respectively for small, large and very large volume disease defined by Medical Research Council criteria, and 91.2% and 60.8%, respectively, for men with low (alpha FP less than or equal to 500 kU/l and HCG less than or equal to 1000 iU/l) or high serum marker levels. 79 men (62%) had a complete radiological and serum marker response to chemotherapy alone; residual masses postchemotheraphy were resected in 39 patients (31%), showing undifferentiated tumour in only 6 (15%). 23 of the 127 patients (18%) failed to respond or developed recurrent disease after BEP; only 5 were successfully salvaged. Myelotoxicity of treatment was mild with grade 4 toxicity in 2% of chemotherapy courses and 3 episodes of neutropenic sepsis. Mean glomerular filtration rates fell by 15.6% between courses 1 and 4 of BEP. Bleomycin pneumonitis developed in 13% of cases with 1 fatality. So far 21 men have had children following chemotherapy, but semen analysis 12 months or more (median 36 months) after treatment showed azoospermia in 11 out of 54 (20%) men tested. BEP chemotherapy can be regarded as standard treatment for patients with metastatic NSGCT in low-risk categories, but more intensive therapy is required for advanced presentations. Strategies to develop "risk related" treatment are under investigation.

Effectiveness of carboplatin, etoposide, and bleomycin combination chemotherapy in good-prognosis metastatic testicular nonseminomatous germ cell tumors.

The combination of carboplatin, etoposide, and bleomycin (CEB) was evaluated as initial chemotherapy in 76 patients with good-prognosis metastatic nonseminomatous germ cell tumors (NSGCT) between 1984 and 1988. The classification of eligible patients included Royal Marsden Hospital (RMH) stages IM, IIA, IIB, IIC, IIIA, IIIB, IV0ABCL1, and IV0ABL2. Four courses of combination chemotherapy were administered in a 21-day cycle, and surgical excision of residual mass was performed in 27 cases (23 laparotomies and four thoracotomies). At the time of analysis, median follow-up was 24 months from start of chemotherapy (range, 6 to 54 months). The 2-year cause-specific survival probability was 98.5%, the single cause-related mortality being caused by bleomycin pneumonitis. Five patients failed CEB chemotherapy, but all have been successfully salvaged with a combination of surgery and intensive chemotherapy, follow-up from completion of all treatment being 35 to 44 months. The toxicity of CEB included bone marrow suppression and alopecia in all patients but no significant neurotoxicity or ototoxicity, and minimal renal toxicity. Only four (5%) patients had a decrease in the glomerular filtration rate greater than 15%. In 51% of patients, the hemoglobin fell below 10 g/dL. The WBC count nadir was less than 1,500/microL in 11% of treatment cycles and in 16% the platelet nadir fell below 50,000/microL. Decreases in the WBC and platelet counts were of very brief duration. Only one of 310 CEB cycles was complicated by neutropenic sepsis, and there were no episodes of thrombocytopenic purpura or bleeding. We conclude that the CEB combination represents an effective alternative to cisplatin-based chemotherapy in good-prognosis NSGCT and that the replacement of cisplatin by carboplatin leads to reduced toxicity.

Orchidectomy alone for stage I seminoma of the testis.

Between 1983 and 1988, 113 patients with Stage I seminoma were managed after orchidectomy by surveillance rather than adjuvant radiotherapy. The actuarial risk of relapse at 3 years was 15.8% (95% confidence interval, 7.8% to 23.8%). All 13 patients who experienced a relapse are currently in remission (4 to 45 months after salvage therapy), although 5 suffered second relapses requiring further treatment. Close surveillance is a safe alternative to adjuvant radiotherapy in Stage I seminoma. However, the policy requires prolonged observation of patients with intensive use of resources. Therefore, adjuvant radiotherapy should be considered the treatment of choice.

Simple nontoxic treatment of advanced metastatic seminoma with carboplatin.

Between 1982 and 1986, 34 patients with advanced metastatic seminoma were treated with four to six courses of single-agent carboplatin administered at 400 mg/m2 every 4 weeks either on an outpatient basis or during 24-hour admissions. Patients with raised serum alphafetoprotein (AFP) or with multiple (more than three) lung metastases were excluded since these features may indicate a nonseminomatous component. In this series 20 patients were previously untreated except for orchiectomy, and 14 patients had received prior radiotherapy restricted to infradiaphragmatic nodal areas. Treatment was extremely well tolerated. No patient suffered renal damage, neurotoxicity, or ototoxicity, and there were no episodes of neutropenic septicemia, thrombocytopenic hemorrhage, or bruising. The actuarial 2-year survival was 94% (95% confidence intervals, 83% to 100%) with follow-up of 12 to 46 months from completion of carboplatin (mean, 26 months). The actuarial chance of remaining alive and free from progressive disease at 2 years was 80% (95% confidence intervals, 66% to 94%). Of six patients who relapsed, five are currently in remission 9 to 18 months after completion of salvage treatment. This level of antitumor activity is equivalent to that seen with aggressive combination regimens. Single-agent carboplatin should be considered the treatment of choice for advanced stages of malignant seminoma when limitation of toxicity is considered important; however, the rarity, especially of extranodal metastases from seminoma, leads to the need for further investigation using this approach.

Stage III Hodgkin's disease--long-term results following chemotherapy, radiotherapy and combined modality therapy.

215 patients with stage III Hodgkin's disease (HD) were treated at the Royal Marsden Hospital between 1963 and 1985 (median follow-up 9 years). The actuarial 5- and 10-year survival was 77 and 65%, respectively with 55 and 48% 5 and 10 year disease-free survival. Of 13 variables tested, age was the only independent prognostic indicator for survival on multivariate analysis. Patients aged under 40, 40-59 and over 60 years had a 10-year survival of 76, 41 and 8%, respectively (p much less than 0.001). Ninety-one patients were initially treated with combined chemotherapy and radiotherapy (combined modality therapy, CMT), 73 patients with radiotherapy (RT) and 51 patients with chemotherapy (CT) alone. Patients under 40 years treated with CMT achieved the best disease-free survival (10 year disease-free survival: CMT 68%; RT 38%; CT 45%). The observed survival advantage for CMT was not statistically significant. In patients aged greater than 40 there was no survival or disease-free survival advantage following CMT. Analysis of recurrence pattern confirmed that CMT improves initial disease control both at previously involved and uninvolved sites. Recurrences at previously uninvolved sites continued up to 6 years following CT, up to 8 years following CMT and up to 14 years after RT alone. These results indicate that only long-term follow-up gives the true picture of stage III HD.

Intensive induction chemotherapy for poor risk non-seminomatous germ cell tumours.

An increase in initial chemotherapy intensity was evaluated in 29 patients with high risk metastatic non-seminomatous germ cell tumours (NSGCT) of the testis, defined by the presence of multiple large lung metastases, liver, bone or brain metastases, or the combination of large abdominal mass with high serum concentration of the tumour markers alpha-foetoprotein (AFP) or beta subunit of human chorionic gonadotrophin (HCG) (AFP greater than 500 ku/l or HCG greater than 1000 iu/l). Four courses of bleomycin, vincristine and cisplatin (BOP) were given at 7 day intervals, followed by three courses of etoposide, cisplatin with or without bleomycin (BEP or EP) at 21 day intervals for a total of 13 weeks of chemotherapy. Twenty-three (85%) of 27 evaluable patients have remained continuously free from disease progression at a median of 24 months (range 14-38 months) from chemotherapy and the actuarial 2 year freedom from progression rate is 86% (95% CI = 73-99%). Three patients died from non-malignant causes, two of bleomycin pneumonitis and one from complications of cystic fibrosis. Thus cause specific overall survival in the total population of treated patients is 79%. With appropriate limitation of bleomycin dosage, this approach is well tolerated and results compare favourably with less intensive induction schedules based on initial 21-28 day cycles.

The management of advanced testicular teratoma.

Of 320 patients with metastatic malignant non-seminomatous germ cell tumours of the testis (NSGCT) treated with chemotherapy, 266 (83%) are alive and well after a median follow-up of 39 months. Deaths from treatment-related causes occurred in 9 patients and were related to intensity of chemotherapy. Relapse after chemotherapy was rare except in presentations with large tumour volume and high serum marker concentrations and a strategy has been developed of risk-related choice of chemotherapy in order to reduce treatment toxicity in good prognosis sub-groups of patients.

Second malignancies and Hodgkin's disease--the Royal Marsden Hospital experience.

The frequency of secondary malignant neoplasms occurring in patients treated for Hodgkin's disease at the Royal Marsden Hospital between 1963 and 1978 is reported and the literature is reviewed. 730 patients were reviewed and 583 patients permanently resident in the United Kingdom were included in the analysis. The frequency of leukaemia and solid tumors was determined from age- and sex-corrected data from the South Thames Cancer Registry. Thirty-seven malignancies were recorded in 36 patients including 9 leukaemias, 10 lung cancers, 6 skin cancers and 2 non-Hodgkin's lymphoma, all of which were observed in significant excess. When all remaining sites are combined, there was a slight excess but no one site is individually significant.

Medical options in the management of stages 1 and 2 (N0-N3, M0) testicular germ cell tumors.

Retroperitoneal lymph-node dissection or radiotherapy have long been known to provide equivalent survival for early stage I and stage II nonseminomatous germ-cell tumors. Review of the results from intensive radiological and biochemical surveillance with salvage chemotherapy for stage I tumors demonstrates that the long-term survival rate is equivalent to that achievable by conventional treatment (i.e., 98 per cent survival at 4 years). As relapses have continued to occur in the third and fourth years at the rate of 4 per cent annually, and 4 years is the limit of follow-up, further follow-up is required to be sure of the long-term picture. Prognostic factor analysis demonstrates that venous and lymphatic invasion, the absence of yolk sac differentiation, and the presence of undifferentiated cells are independently important in predicting the frequency of relapse. Using these factors, it was possible to define low-risk groups with relapse rates less than that seen after lymph-node dissection and high-risk groups with 58 per cent frequency of relapse who probably are suitable for adjuvant chemotherapy studies. Review of the results from the use of surveillance in stage I seminoma demonstrated no advantages over prophylactic radiotherapy. However, late toxicity is being demonstrated after radiotherapy and evidence is emerging that the less toxic cisplatinum analogue carboplatin may be as good as radiotherapy for metastatic disease. This offers for the first time a viable alternative to radiotherapy for consideration in the adjuvant setting in stage I seminoma.

Gastrointestinal morbidity of adjuvant radiotherapy in stage I malignant teratoma of the testis.

Between January 1963 and December 1983, 248 patients with stage I teratoma were managed by the Testicular Tumour Unit of the Royal Marsden Hospital (RMH). Before 1979, these patients were treated with adjuvant irradiation to the abdominal and pelvic lymph nodes (142 patients) to a mid-plane dose of 40 Gy in 20 fractions over 4 weeks. In 1979, a surveillance policy was adopted (106 patients) and relapsing patients treated with chemotherapy. By 2 years post-orchidectomy, seven patients (4.9%) in the irradiated group developed duodenal ulceration compared to none in the surveillance group (p = 0.05). A past medical history of duodenal ulcer was a significant risk factor for ulceration after radiotherapy (p = 0.04) whereas a past history of abdominal surgery was not (p = 0.8). It is concluded that adjuvant radiotherapy for stage I teratoma may increase the risk of peptic ulceration.

Histopathology in the prediction of relapse of patients with stage I testicular teratoma treated by orchidectomy alone.

259 patients with stage I non-seminomatous germ-cell testicular teratoma who were treated by orchidectomy alone and monitored at one often centres in the United Kingdom were followed for a median of 30 months. 62 of the 70 relapses occurred in the first 18 months after orchidectomy. The 2-year relapse-free rate was 74%, falling to 68% at 4 years. Histological sections from 233 of the orchidectomy specimens were reviewed centrally. Four features independently predicted relapses: invasion of testicular veins, invasion of testicular lymphatics, absence of yolk-sac elements, and presence of undifferentiated tumour. An index, based on the number of these features observed, identified a high-risk subgroup of 55 patients who had a 42% relapse-free rate at 2 years.

Circulating lymphoma cells in patients with B & T non-Hodgkin's lymphoma detected by immunoglobulin and T-cell receptor gene rearrangement.

We studied peripheral blood mononuclear cells from 50 patients with active B- and T-cell non-Hodgkin's lymphoma by DNA hybridisation. Nineteen patients (38%) had circulating clones of cells detected by immunoglobulin gene rearrangement (17 patients) or T-cell receptor gene rearrangement (2 patients) with JH and J beta 2 probes. Lymphoma tissue and peripheral blood were studied simultaneously in 22 patients, 9 of which had a circulating clone of cells in peripheral blood. In 7 patients the gene rearrangement in lymphoma tissue and peripheral blood mononuclear cells was identical. However, in 2 patients both heavy chain and light chain gene rearrangements were different in tissue and peripheral blood. The incidence of peripheral blood involvement was commonest in advanced CSIII & IV disease (54%) compared to CSI & II disease (18%) (P less than 0.05), and in low grade (45%) compared to intermediate and high grade lymphoma (31%) (difference not statistically significant). Only 4 patients had definite lymphoma cells seen on peripheral blood smear. The presence of circulating lymphoma cells correlated with conventional assessment of bone marrow involvement although circulating clones were detected in 30% (12/40) of patients with apparently normal bone marrow.

Prognosis following chemotherapy for metastatic malignant teratoma.

A multiple regression analysis was performed of factors affecting the prognosis of 93 patients with metastatic malignant teratoma treated at the Royal Marsden Hospital between 1979 and 1981. In a subgroup of 53 patients, where exact tumour bulk could be calculated from sequential CT scan slices, a correlation was seen between tumour marker level and volume of metastatic disease. On analysis of the risk of relapse after initial chemotherapy, the independent adverse influence was detected of serum AFP greater than 500 micrograms/l and of bulky disease defined by clinical staging. An adverse influence of high serum HCG levels was not seen, probably due to the small number of patients in this series with this presenting feature.

Treatment of favorable-prognosis nonseminomatous testicular germ cell tumors with etoposide, cisplatin, and reduced dose of bleomycin.

We have explored a dose reduction of bleomycin in combination with etoposide and cisplatin in the treatment of a good-prognosis subgroup of patients with nonseminomatous germ cell tumors. Twenty-two patients were treated with etoposide, cisplatin, and low-dose bleomycin. All patients achieved complete remission, but four relapsed. Three patients achieved long-term remission after salvage therapy. The disease-free survival rate of 82% (18 of 22 patients) at a median follow-up of 24 months (range, 17-33) was significantly worse compared to the 99% disease-free survival rate in 91 patients receiving full-dose bleomycin, etoposide, and cisplatin. These results are similar to a previously reported 82% disease-free survival rate of 17 patients treated with etoposide and cisplatin alone. The combined results of the 82% disease-free survival rate in the total group of 39 patients treated with etoposide and cisplatin and etoposide, cisplatin, and low-dose bleomycin suggest that the reduced bleomycin regimens in their present schedule constitute inadequate therapy.

Chemotherapy of germ-cell ovarian tumours: first-line treatment with etoposide, bleomycin and cisplatin or carboplatin.

Of 9 patients with malignant ovarian germ-cell tumours (OGCT) treated with combination chemotherapy between 1980 and 1985, 8 are alive and disease-free at 6-62 months. All patients received etoposide and bleomycin and 8 out of 9 also received a platinum analogue; in one case carboplatin, in a second carboplatin plus cisplatin, and in the remainder, cisplatin. In one patient treated prior to the introduction of carboplatin, poor renal function precluded the use of cisplatin. Two patients with Stage III dysgerminomas are disease-free at 44 and 62 months after receiving chemotherapy followed by radiotherapy to the whole abdomen or pelvis. Of 7 patients with non-dysgerminomatous OGCT, including 2 dysgerminomas with raised serum alphafetoprotein, 6 are disease-free at 6-56 months. On the basis of these observations and experience reported elsewhere, surveillance after removal of the primary tumour is proposed for early-stage dysgerminoma, and chemotherapy is suggested for advanced presentations as an alternative to surgery and post-operative radiotherapy. Combination chemotherapy is indicated for all stages of non-dysgerminomatous OGCT.