J. Nicholls

Fertility after chemotherapy for testicular germ cell cancers.

PURPOSE To analyze the probability of recovery of spermatogenesis after orchidectomy and cisplatin-based chemotherapy (CT) for testicular germ cell cancer. PATIENTS AND METHODS One hundred seventy-eight patients treated between 1979 and 1991 were selected by the requirement of sperm count both pre-CT and post-CT. Counts were classified as normospermic (NS) if more than 10 x 10(6)/mL, oligospermic (OS) if 1 to 9 x 10(6)/mL, and azoospermic (AS) if less than 1 x 10(6)/mL. The median follow-up time after CT before sperm analysis was 30 months. RESULTS Analysis of 170 patients whose spermatogenesis was reassessed at least 1 year after CT showed that of 89 patients whose pre-CT counts were NS, the post-CT count was NS in 64%, OS in 16%, and AS in 20%. There was clear evidence for continued recovery beyond 1 year; the probability of spermatogenesis increased to 48% by 2 years and 80% by 5 years. There was a significantly higher probability of recovery to OS and NS count levels in the 54 patients treated with carboplatin-rather than cisplatin-based therapy. There was an independent and similar effect of normal pre-CT count. There was a reduced probability to recover to OS in the 26 patients treated with more than four cycles of CT. A prognostic model identified three groups with 25%, 45%, and 82% probabilities of recovering spermatogenesis by 2 years after CT. CONCLUSION Analysis of pre-CT sperm count together with details of planned treatment can be used to predict recovery of spermatogenesis following germ cell CT.

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.

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.

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.

Primary chemotherapy for stage II nonseminomatous germ cell tumors of the testis.

Between 1979 and 1989, 122 patients with clinical stage II testicular nonseminoma were treated with primary platinum-based combination chemotherapy following orchiectomy. Of the patients 58 had Royal Marsden Hospital stage IIA (nodes less than 2 cm. in diameter) and the other 64 had stage IIB (nodes 2 to 5 cm. diameter) disease. With a median followup after chemotherapy of 5.5 years, 118 patients (97%) were disease-free. Two patients died of progressive germ cell tumors, 1 of bleomycin toxicity and 1 of coincidental disease. The 5-year actuarial survival probability was 95% (95% confidence intervals 91 to 99%) and the 5-year failure-free survival probability was 92% (95% confidence intervals 88 to 97%). Tumor substage was not predictive of relapse but did indicate the probability of lymphadenectomy for a post-chemotherapy residual mass since this was performed in 17% of the patients with stage IIA disease and 39% with stage IIB disease (p < 0.05). Resected specimens contained mature teratoma (29), necrosis alone (5) or embryonal carcinoma (1). We conclude that for these clinical stages primary chemotherapy was as effective as primary lymph node dissection and a major operation was avoided in 68% of the cases.

The activity of single-agent carboplatin in advanced seminoma

Between 1982 and 1990, 70 patients with advanced metastatic seminoma were treated with 4-6 courses of single-agent carboplatin (SAC) administered at 400 mg/m2 every 3-4 weeks. Treatment was of low toxicity and no patients suffered neurotoxicity, ototoxicity or significant renal damage. There was only one episode of neutropenic sepsis and no thrombocytopenic bleeding. The median follow-up of surviving patients was 3 years. 16 patients have relapsed and 4 of these 16 have died, thus the actuarial 3-year relapse-free survival was 77% (95% CI 65-86%), cause-specific survival was 94% (95% CI 82-99%) and overall survival was 91% (95% CI 80-96%). The risk of relapse was reduced by post-chemotherapy irradiation (PCRT) to involved nodes, occurring in 1/20 patients treated with PCRT compared with 11/31 who could have been treated but were not (P = 0.04). Of the 16 patients who relapsed, 12(75%) have been salvaged with combination chemotherapy and remain free from further relapse with a median follow-up of 18 months. Though this level of survival is equivalent to that obtained with initial cisplatin-based combination chemotherapy, the recurrence rate indicates that SAC remains an investigative treatment, except for unfit patients.

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).

Does extragonadal presentation impart a worse prognosis to abdominal germ-cell tumours?

The prognostic significance of extragonadal rather than gonadal presentation of germ-cell tumour in 51 patients presenting between 1979 and 1988 with abdominal tumours was compared with that of 51 control patients with testicular primary tumours matched for bulk fo disease, serum tumour marker concentration, age and year of treatment. Very large volume tumour was found at initial staging in 24 extra-gonadal cases (47%) and high tumour markers in 29 (57%). Actuarial survival at 2 and 5 years was 82% and 70% for cases and 78% and 63%, respectively, for controls. These outcomes were not significantly different and the relative hazard of death for cases compared with controls was 0.7 (95% confidence intervals 0.3-1.5). Thus the presentation of germ-cell tumours with a retroperitoneal mass does not itself adversely influence prognosis compared with testicular presentation with equivalent disease extent. However it is rare for extragonadal presentation to be associated with small volume disease.

Multivariate Analysis of Predictive Factors of Late Relapse in 1264 Patients with Testicular Germ Cell Tumours

10–30 per cent of patients with testicular germ cell tumours (GCTs) relapse after initial treatment. Most of these relapses happen in the first two years after treatment.

Factors Associated with Bleomycin Lung Toxicity in Germ Cell Tumour Patients Treated at the Royal Marsden Hospital Between 1982 and 1999

Bleomycin is a polypeptide antibiotic, anti-neoplastic agent, which has been used in the treatment of germ cell tumours for over 20 years. Pulmonary toxicity has been known since the early clinical trials in the 1960’s.There are a surprisingly few large studies examining risk factors for bleomycin lung toxicity in germ cell cancers. Suggested risk factors include cumulative dose, reduced renal (EDTA) clearance, raised creatinine, age of patient, and major surgery.