G. J. S. Rustin

Developments in chemotherapy for medium‐ and high‐risk patients with gestational trophoblastic tumours (1979–1984)

Summary. Identification of various prognostic factors at the start of chemotherapy allows patients with gestational trophoblastic tumours to be categorized into low‐, medium‐ and high‐risk groups so that they can be given the minimum treatment necessary to eliminate their disease. Most patients in the low‐risk category can be treated with minimal toxicity using a methotrexate/folinic acid regimen and these patients are not considered in this report. Before 1979 patients in the medium‐risk category were treated with a sequence of drugs which included, hydroxyurea, methotrexate, 6‐mercaptopurine, actinomycin D, vincristine and cyclophosphamide. Since 1979 etoposide has been substituted for vincristine and cyclophosphamide. The 76 patients treated between 1979 and 1983 are all alive and in remission 1·1.85. Three patients (4%) relapsed and required retreatment and all are in remission. Fifty‐six patients in the high‐risk group, most at risk of developing drug resistance, were treated with a regimen incorporating etoposide with methotrexate, actinomycin D (EMA) and vincristine and cyclophosphamide (CO). EMA and CO were given on alternate weeks, resulting in an overall survival rate of 84%. Patients who had received prior chemotherapy had a survival rate of 74% and a relapse rate of 19% compared with 93% survival and 3% relapse rate in those who had not received prior chemotherapy. Toxicity with the EMA/CO regimen was significantly less than with an earlier regimen (CHAMOCA) used in the high‐risk group.

Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to 1989

Objective— To assess the efficacy, toxicity and survival in patients with high risk GTT treated with the EMA/CO regimen (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine/oncovine).

Further advances in the management of malignant teratomas of the testis and other sites.

Between 1979 and 1982, 69 men with metastatic malignant teratoma completed sequential combination chemotherapy (POMB/ACE). Although two-thirds of these patients initially had advanced and bulky disease, life-table analysis projects a survival of 83%. Multivariate analysis indicates that the strongest predictor of survivals is not the clinical and radiological extent of disease but the initial serum concentration of human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP). In patients presenting with HCG levels below 50 000 IU/l and AFP levels below 500 kU/l the survival in 47 patients was 96%. This contrasts with the survival projected at 56% in 22 patients presenting with tumour markers at higher concentrations.

The role of low‐dose methotrexate and folinic acid in gestational trophoblastic tumours (GTT)

Summary. Between 1964 and 1986, 487 patients with gestational trophoblastic tumour (GTT) were treated with methotrexate and folinic acid. The patients comprise two groups: between 1964 and 1974, 126 patients were treated but were not systematically stratified using a prognostic score before the start of treatment. These patients formed part of the 317 women who were analysed to identify a number of prognostic variables (Bagshawe 1976). Retrospective analysis of these 126 patients using these prognostic factors showed that in the true low‐risk group 85/88 (96%) are alive while 20/22 (91%) of the medium‐risk group and only 5/16 (31%) of the high‐risk group are alive. Overall the survival was 110/126 (87%) with a minimum follow‐up of 14 years. From 1974 all patients were stratified on admission into prognostic groups. Of the true low‐risk patients 347/348 survived (99·7%); 13 patients were underscored and treated as low risk when they should have been treated as medium risk, 12 (92%) of these are alive, but nine (69%) needed to change treatment because of drug resistance. While the overall survival in the 1974–1986 group was 359/361 (99%) with a minimum follow‐up of 16 months, the survival in all patients (1964–1986) was 469/487 (96%). Although the survival in these patients is excellent it should be noted that 69/348 (20%) low‐risk patients had to change treatment because of the development of drug resistance, and a further 23 (6%) needed to change treatment because of drug‐induced toxicity. Low‐dose methotrexate and folinic acid given in the schedule described remains the treatment of choice in patients with low‐risk GTT because of its effectiveness and minimal short‐ and long‐term toxicity. Patients presenting with medium‐ and high‐risk GTT need to start with combination chemotherapy from the outset to avoid the development of drug resistance.

Central nervous system metastases of choriocarcinoma. 23 years' experience at Charing Cross Hospital.

Between 1957 and February 1981, 782 patients received cytotoxic chemotherapy for gestational trophoblastic tumors (GTT) in the Department of Medical Oncology, Charing Cross Hospital (London, England). Sixty‐nine (8.8%) patients had central nervous system (CNS) metastases. Thirty‐three of them (48%) presented with CNS disease prior to treatment (CNS presentation group), and 36 (52%) developed CNS disease while on treatment, or relapsed in the CNS after an initial complete or partial remission (late CNS group). Treatment included systemic and intrathecal chemotherapy, and, in several cases neurosurgery, whole brain irradiation, and immunotherapy. Life‐table analysis projects an overall survival of 49% for the CNS presentation group and 6% for the late CNS group. Prognosis has improved with time; prior to 1974, 38% of the CNS presentation group and none of the late CNS group survived. After 1974 overall survival has been 80% in the CNS presentation group and 25% in the late CNS group. The principal elements in the successful management of such cases are: (1) CNS prophylaxis with intrathecal methotrexate for patients at risk of developing brain metastases; (2) early detection of CNS lesions by prompt recognition of their clinical features, measurement of the ratio of CSF to serum human chorionic gonadotropin concentration, and appropriate use of computerized tomography of the brain; and (3) a combination of systemic and intrathecal therapy for patients developing brain secondaries.

Presentation and management of choriocarcinoma after nonmolar pregnancy

Objective To ascertain the mode of presentation and treatment outcome for women with choriocarcinoma after a nonmolar pregnancy.

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.

We analysed outcome in 206 consecutive male patients treated for metastatic non-seminomatous germ cell tumour (NSGCT) of testicular or extragonadal origin treated with the POMB/ACE (cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, etoposide) regimen after division into prognostic groups by commonly used clinical classification systems and definitions of adverse prognosis. The adverse prognostic groups of all classification systems and definitions examined showed similar, but only moderate, sensitivity (71-81%) and specificity (52-56%) in predicting death. A simple definition of poor prognosis based on raised initial levels of serum tumour markers alpha fetoprotein (aFP) and human chorionic gonadotrophin (hCG) proved at least as useful (sensitivity 80%, specificity 55%) as other more complicated systems in predicting failure to achieve long-term survival. Comparison of survival between ultra-high dose cisplatin-based combination chemotherapy and patients treated with POMB/ACE shows no advantage from this more toxic approach. This suggests that good results in adverse prognosis patients can be achieved using conventional dose regimens administered intensively.

Potential for cure in metastatic ovarian teratomas and dysgerminomas

Summary. Between 1977 and 1981 21 patients with metastatic ovarian germ cell tumours received sequential combination chemotherapy; 18 had malignant teratomas and three dysgerminomas. Thirteen patients with malignant teratoma have had no treatment for up to 45 months (mean 27.5 months) and one patient is still having treatment. Life table estimate of survival on 1 July 1981 projects a survival of 71% in those with malignant ovarian teratomas. Four patients with malignant teratoma have died. Two of these had received extensive treatment before referral and a third achieved complete remission but relapsed and did not subsequently respond fully to further treatment. A fourth patient had an undifferentiated tumour compatible with an embryonal carcinoma which proved refractory to all treatment. The three patients with advanced dysgerminomas are all in remission and have had no treatment for 5, 14 and 33 months respectively. The majority of metastatic germ cell tumours of the ovary now appear to be curable provided that effective treatment is begun early.

Successful treatment of patients in whom germ cell tumour masses enlarged on chemotherapy while their serum tumour markers decreased

Enlargement of tumour masses with a fall or no change in tumour marker levels was noted in eight of 287 patients during chemotherapy for NSGCT at the Charing Cross and Mount Vernon Hospitals between 1977 and 1988. These eight patients had elements of differentiated teratoma in the primary specimen and in five the enlarging masses showed cystic change on CT scan. The increase in tumour mass occurred within 6 months of starting treatment. At surgery, four patients were found to have differentiated teratoma and have been followed for 15 months to 5 years without relapse. Two patients who also had some areas of embryonal carcinoma in the resected specimens had post-operative chemotherapy and are alive disease free at 8 and 24 months respectively. Two patients died: one post-operatively of uncontrolled haemorrhage secondary to aortic rupture and the second of acute myeloid leukaemia following 8 years of intermittent therapy for unresectable differentiated teratoma. The successful outcome in six of these eight patients suggests that enlarging teratomatous masses on chemotherapy can be managed by surgical resection and, when active tumour is present, by the use of post-operative chemotherapy.

Fertility after chemotherapy for ovarian germ cell tumours

Gonadal function was assessed in 17 women who successfully completed chemotherapy with the POMB/ACE regimen (cisplatin, vincristine [Oncovin], methotrexate, bleomycin/ actinomycin D, cyclophosphamide, etoposide) for ovarian germ cell tumours, and had a remaining ovary and uterus. A 20‐year‐old girl has not yet recovered menstruation 5 months off chemotherapy. All the remaining women whose mean age at start of chemotherapy was 21 (9–38) are now menstruating with a median time of recovery of 4½ months after completion of chemotherapy. Five women have so far conceived after chemotherapy resulting in three full term normal deliveries of healthy infants, one termination of pregnancy, two miscarriages and one continuing pregnancy. Gonadal function does not appear to be permanently impaired in the majority of patients receiving POMB/ACE chemotherapy for ovarian germ cell tumours.