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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.

A pilot study on 35 women was performed to determine the feasibility of giving whole abdominal radiotherapy after surgery and chemotherapy for Stage III and IV ovarian adenocarcinoma. The planned duration of therapy was only 6 months from diagnosis. Chemotherapy consisted of four courses of cis-platinum 100 mg/m 2 alternating every 10–12 days with four courses of methotrexate 300 mg/m 2 and cyclophosphamide 500 mg/m 2 followed by folinic acid rescue. Twenty-nine of 35 (83%) patients were shown at second look surgery after chemotherapy to have residual tumour deposits no more than 2 cm in diameter. The usual radiotherapy dose was 2400 cGy in 20 fractions over approximately 4 to 5 weeks, with kidney shielding, and was generally well tolerated. Three patients failed to complete radiotherapy, two because of progressive disease and one because of persistent nausea and vomiting. During radiotherapy the white blood count fell below 2.0 × 10 9 /litre in seven patients (26%), and in eight patients (30%) the platelet count fell below 75 × 10 9 /litre. However, the white blood count nadir of 1.5 × 10 9 /litre was reached by 1300 cGy and the platelet nadir of 45 × 10 9 /litre was reached by 1400 cGy and both then levelled or recovered despite continuing radiotherapy. The median follow up since diagnosis is 26 months. Four of 12 patients with no tumour detected at second look operation have relapsed compared with 13 of 15 patients who had detectable tumour. Toxicity of this multi-modality therapy was acceptable.

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 survival 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/1 and AFP levels below 500 kU/1 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.

We investigated the incidence of second tumors after cytotoxic chemotherapy in 457 long-term survivors treated for choriocarcinoma or an invasive mole between 1958 and 1978. Treatment was given according to regular intermittent schedules and over a mean period of four months, with no maintenance. Methotrexate was given to all but two patients, and 261 (57 per cent) also received other cytotoxic drugs, most commonly dactinomycin, vincristine, cyclophosphamide, mercaptopurine, and 6-azauridine. After a mean period of 7.8 years since the beginning of treatment and a total of 3522 patient-years of risk, second neoplasms had developed in only two women (acute leukemia in one and carcinoma of the breast in the other). This figure is less than the number of cases of cancer that would have been expected (3.5) in this group and suggests that the use of methotrexate as chemotherapy for choriocarcinoma is not carcinogenic in the medium term.

Gonadal function was assessed in fifty-nine men and thirty-one women who had successfully completed chemotherapy with the POMB/ACE regimen for germ cell tumours. Seventeen (81%) of the twenty-one men who had not received paraaortic radiotherapy, whose original tumour bulk was less than 5 cm and whose duration of chemotherapy was less than 6 months, recovered spermatogenesis compared with twelve (32%) of thirty-eight patients who had either larger tumour masses or longer courses of chemotherapy, or both. All but one of the seventeen women in whom menstruation could have been expected to recur are now menstruating. This study suggests that the great majority of patients treated with POMB/ACE chemotherapy for germ cell tumours will recover fertility.

In a series of 114 stage 1 testicular tumour patients managed by a surveillance policy there have been 26 relapses. Three of these patients presented with lumbar pain as the first sign of relapse. All 3 were tumour marker non-producers and the onset of pain pre-dated radiological abnormality by up to 4 months. Stage 1 surveillance patients who develop lumbar pain must be considered to be at high risk of relapse to avoid delay in diagnosis which may prejudice survival.

Twenty patients with advanced testicular teratoma and 1 with advanced seminoma have undergone abdominal surgery for the removal of residual disease following treatment by sequential chemotherapy (1). Fourteen out of the 21 patients (66 per cent) have achieved complete remission with a follow-up period of 6–41 months. In 12 patients (57 per cent) the tumour had undergone histological maturation or necrosis following chemotherapy, those patients in whom the tumour remained histologically active having a worse prognosis. Raised preoperative serum levels of the tumour markers human chorionic gonadotrophin (hCG) and alpha-fetoprotein (AFP) indicating active disease, forecast a particularly poor prognosis, 5 out of 9 such patients (55 per cent) having died. Computerized tomography gave false negative results in 3 patients (14 per cent). Postoperative complications were few, and only 2 patients (9 per cent) suffered with failure of ejaculation. At present our policy is surgical removal of any residual mass after chemotherapy to determine the histology, and, wherever possible, to achieve complete clinical and biochemical remission. Six patients with an apparently poor prognosis have benefited directly from surgery and remain in long term remission. The selection of patients who benefit most from surgery can only be determined by more experience and longer follow up.

Elevated serum carcinoembryonic antigen (CEA) prior to specific treatment was noted in 3% (7/258) of assessable patients with testicular, extragonadal or ovarian germ cell tumours (GCT). In addition, persistently raised CEA was documented in 7% (26/385) of patients during or after cisplatin-based chemotherapy for metastatic GCT. Raised CEA did not appear associated with adverse prognosis. Among patients undergoing resection of residual tumour masses post-chemotherapy, 8 of 36 with mature differentiated teratoma excised had raised CEA compared with only one of 39 patients where no mature teratoma was found. However, CEA levels remained elevated in 6 of the 8 cases despite apparent complete resection of mature teratoma. Elevated CEA in treated GCT patients may be caused by hepatotoxicity from chemotherapy, intercurrent diseases, or other unknown factors. History of cisplatin-based chemotherapy may be a confounding factor in interpreting raised CEA levels. CEA measurements do not help in the management of patients with germ cell tumours.

Although virtually 100% of women who develop gestational trophoblastic tumors enter a long-term complete remission, there are many aspects of trophoblastic disease that arouse interest. Epidemiological studies have shown a large geographical variation in the percentage of conceptions that result in a hydatidiform mole and have stimulated studies on the immunological differences of the low and high risk populations. Chromosomal analysis is now complementing the pathological differentiation between complete and partial moles. There is still debate as to which factors are positively associated with the progression of a hydatidiform mole through invasive mole to choriocarcinoma. There are also considerable differences in the proportion of molar patients receiving chemotherapy in different centers. In addition to these topics, this article will review several recently introduced treatment regimens which show improved results with reduced toxicity.

Between 1977 and 1986, 170 male patients with anaplastic germ cell tumours (AGCT) completed chemotherapy with POMB/ACE (platinum, vincristine (oncovin), methotrexate, bleomycin, actinomycin D, cyclophosphamide and etoposide). By increasing the number of courses of POMB in 1979 we have been able to compensate for adverse prognostic factors. Since then each patient has received a minimum of three courses of POMB and 139 patients have completed therapy with an overall survival of 89%, and for those patients who had not received prior radiotherapy the survival is 92%. By increasing the number of courses of POMB, the initial serum concentrations of human chorionic gonadotrophin (hCG greater than 50,000 IU/I) and/or alpha-fetoprotein (AFP greater than 500 kU/l) have ceased to be poor prognostic variables. Neither stage at presentation nor the volume of metastatic disease is a major adverse prognostic variable using this chemotherapy.

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.

Summary. Chemotherapy was given as initial therapy to 12 women with very advanced squamous cell carcinoma of the cervix and to 19 women with recurrent disease. They received a median of four courses of POMB which comprised vincristine 1.0 mg/m2 and methotrexate 300 mg/m2 followed by folinic acid rescue, bleomycin 30 mg as a 48-h infusion or intramuscular injection and cisplatin 100 mg/m2 as a 12-h infusion. Two of the 14 assessable patients with recurrent disease (14%) had a complete response with no disease found histologically in one, and seven (50%) had a partial response. Although the actuarial median survival of all 19 patients with recurrent disease was 8 months, five patients have remained free from tumour progression for a median of 17 months from start of chemotherapy. Six of the 10 assessable patients receiving initial chemotherapy (60%) had a complete response (confirmed histologically in two) and two (20%) had a partial response. Nine patients had additional treatment with radiotherapy and or surgery. Although only four of the patients remain disease-free at 61, 51, 7 and 4 months, all but two were initially FIGO stage IV. Although cisplatin-induced emesis is controllable and the side-effects of methotrexate can be avoided, the POMB regimen remains potentially toxic. The small number of patients with very advanced disease who are long-term survivors prompts us to study further the role of aggressive chemotherapy as the initial treatment of patients with visceral or nodal involvement from carcinoma of the cervix.

We have treated eight patients with various tumours producing hCG or AFP with the high risk gestational choriocarcinoma regimen EMA/CO. Marker response was seen in two of three tumours producing AFP and in all of five tumours producing hCG. Three further patients were treated with EpPt/OMB, a regimen used in relapsed germ cell tumors. All responded biochemically. All complete biochemical responses were accompanied by anatomical response. These responses may reflect particular sensitivity in the marker producing tumours and marker measurements would identify this subgroup. These findings do not preclude the possibility that these cytotoxic regimens may have activity against a wide range of solid tumours.

Summary 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.

The prognostic value of serum CA-125 measurements was assessed in 54 patients with advanced ovarian adenocarcinoma. All patients received a minimum of two courses of carboplatin as part of the North Thames Cooperative Group trial. With a minimum follow-up of 6 months, 37 patients (69%) have clinical evidence of progressive disease and 28 have died. The absolute prechemotherapy level of CA-125 was of no value in predicting which patients would develop progressive disease. However, the change in CA-125 levels from before chemotherapy to 1 month later, after one course of carboplatin, could be used to divide patients into different prognostic groups. The best discrimination was found by dividing the patients into those who showed a greater than sevenfold decrease in CA-125 levels and those who showed a smaller change. Eight of 14 (58%) patients with a greater than sevenfold decrease in CA-125 levels remain disease-free compared with three of 36 (9%) patients with a lesser fall (P = .0005). The change in CA-125 levels during the first month of chemotherapy may indicate which patients should be offered alternative or symptomatic therapy and which should continue with the currently available toxic chemotherapy.

Summary The mechanism underlying the reduced neutrophil alkaline phosphatase (NAP) activity in chronic granulocytic leukaemia (CGL) has been investigated by in vivo manipulation of CGL neutrophils. These cells, which had almost no alkaline phosphatase activity following collection by leucapheresis, had greatly elevated activities 14–17 h after transfusion into three neutropenic recipients. It is postulated that NAP synthesis in mature neutrophils is controlled by an extrinsic factor and that the levels of this factor is reduced in patients with CGL with high neutrophil counts.

Of 297 patients with metastatic testicular and extragonadal germ cell tumours (GCT), bone involvement was detected clinically in 3% (7/251) of those at first presentation and in 9% (4/46) of relapsed cases. This difference was not statistically significant (95% confidence limits -2%; +14%). Concurrent systemic metastases, commonly involving lung (7/11 cases) and para-aortic lymph nodes (6/11), were present in all patients with bone disease. All affected patients had localized bone pain and lumbar spine was the most frequent site involved (9/11). Spinal cord compression occurred in two patients while a third developed progressive vertebral collapse after chemotherapy and required extensive surgical reconstruction. At median follow-up of 4 years, survival among patients presenting with bone disease (6/7) was similar to overall survival in the whole group (84%) and appeared better than in those with liver (18/26, 69%) or central nervous system (6/9) metastases at presentation. Back pain in metastatic germ cell tumours is often due to retroperitoneal lymphadenopathy but lumbar spine osseus metastases must be recognized early if severe potential complications, such as spinal cord compression, are to be avoided. In this series, bone metastases were not seen in the absence of widespread systemic disease suggesting all solitary bony lesions in GCT patients should be biopsied. Images Figure 1 Figure 2

Case reports are presented on 2 patients to show the importance of following up apparently false positive results of pregnancy tests. In case 1, a 25-year-old woman was admitted to the hospital with severe breathlessness in September 1987. After she had stopped using oral contraceptives (OCs) in 1985 her periods were irregular and on 4 occasions the results of pregnancy tests bought over the counter were positive. She was twice referred for ultrasound examinations, but the uterus was empty each time. In April 1987, dysfunctional uterine bleeding was diagnosed; she was treated with clomiphene. She then experienced intermittent pleuritic chest pain and breathlessness on exertion. In early September she was admitted with acute breathlessness and chest pain. A further pregnancy test was positive; results of laparoscopy of the pelvis were normal. A radioisotope ventilation-perfusion lung scan showed multiple filling defects in the left lung and no perfusion to the right. A presumptive diagnosis of choriocarcinoma was made with the syndrome of tumor growing in the pulmonary arteries. In case 2, a 32-year-old woman was admitted to the hospital in March 1988 with acute lower abdominal pain. A pregnancy test was positive, and she underwent laparoscopy for suspected ectopic pregnancy. A macroscopic tumor was found on the surface of the right ovary and a right salpingo-oophorectomy was performed. A subsequent histological examination showed choriocarcinoma. The 2 cases reported show the importance of seeking a definitive explanation for a false positive result of a pregnancy test. If the test has been performed correctly and proteinuria and drug interference, for instance, are ruled out, then a raised human chorionic gonadotropin concentration, particularly in young women, is virtually certain. In most cases this will be due to a pregnancy that ends in a 1st trimester abortion, but in a small minority it will be due to the hormone producing a tumor such as choriocarcinoma.

The combination of recombinant human interferon alpha A 9 MU daily intramuscularly and etretinate 50 mg daily orally was given to 25 patients with progressive advanced, metastatic melanoma. The treatment was well tolerated. Partial responses were seen in three (12%) patients lasting from 2 to 8 months. A further partial response was seen in one of three patients when they were given vindesine and DTIC whilst they continued receiving interferon and etretinate.

Platinum based combination chemotherapy has been associated with a high response rate in patients with cervical carcinoma. To determine whether the toxicity could be reduced but the efficacy maintained carboplatin 200 mg m-2 was substituted for cisplatin in a regimen that was repeated two weekly and also contained vincristine, methotrexate and bleomycin. Twenty-four patients with squamous cell carcinoma of the cervix of whom 17 had relapsed following radiotherapy were studied. Only 5 of the 19 evaluable patients had a partial response (26%, 95 confidence limits 45.7-6.3%) compared to 30 of 43 (70%, 84-56%) who received a cisplatin combination in a previous study (P less than 0.01) (Rustin et al., 1987). Carboplatin as given in the COMB regimen appears less effective than cisplatin containing combinations for squamous cell carcinoma of the cervix.