A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis.

Forty-four patients with documented meningeal carcinomatosis (small-cell lung carcinoma [SCLC], 29%; breast carcinoma, 25%) were treated in a prospective randomized trial with intrathecal methotrexate (MTX) 15 mg or MTX plus cytosine arabinoside (Ara-C) 50 mg/m2. Most patients received intrathecal hydrocortisone (HC) each treatment to minimize arachnoiditis. Overall response was 55%. Seven patients achieved complete response. Response to MTX was superior to combined MTX/Ara-C, but not significantly so (61% v 45%; P greater than .10). Response was more frequent if drugs were administered via Ommaya reservoir than by lumbar puncture (65% v 48%; P greater than .10). Concurrent radiotherapy to the CNS was associated with significantly better response (73% v 35%; P less than .05). Small-cell lung carcinoma patients showed the best response (69%). Overall median survival for the whole group was 8 weeks, but responders fared better than nonresponders (median survival, 18 v 7 weeks; P less than .05). Nausea and vomiting were the most common toxicities encountered (45%), but rarely proved limiting. An unusual, previously undocumented reaction to intrathecal HC was noted. MTX is moderately effective in nonleukemic meningeal carcinomatosis, but the addition of Ara-C does not appear to improve results. Pretreatment factors did not predict outcome in this trial.

Carcinoembryonic antigen levels in germ cell tumours.

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.

Clinical value of imaging using antibody to alpha fetoprotein in germ cell tumours.

Germ cell tumours (GCT) producing alpha fetoprotein (aFP) can be imaged by external scintigraphy after intravenous administration of radiolabelled antibody directed against aFP. Antibody imaging (AI) by this method was used in an attempt to guide surgical resection of deposits of drug-resistant or recurrent GCT. 30 patients with GCT and raised aFP in whom site of tumour was not known were investigated by AI and conventional imaging methods. All but one were heavily pretreated. Where tumour appeared localised, resection was attempted. Tumour was found in all sites positive by both AI and conventional imaging. AI produced false-positive results in one of 30 patients and false-negative results in 9 patients. Computerised tomography was false-positive in one case and false-negative in three. In these patients, AI gave true-negative and true-positive results, respectively. Of 11 patients with positive AI in whom resection was attempted, 6 achieved sustained complete response with up to 5 years follow-up. We conclude AI and conventional imaging methods to be complementary in selection for surgery of patients with drug-resistant or recurrent GCT.

Encephalopathy following cisplatin, bleomycin and vinblastine therapy for non-seminomatous germ cell tumour of testis.

A 22-year-old man developed severe encephalopathy, grand mal seizures and visual disturbance after combination chemotherapy with cisplatin, vinblastine and bleomycin for metastatic testicular carcinoma. After excluding treatable causes, only supportive management was given, and the symptoms and signs resolved over several months. We suggest a clinical syndrome of encephalopathy, seizures and visual disturbance represents a rare toxicity of cisplatin-based therapy. Given the wide spread usage of cisplatin, this should be drawn once again to the attention of medical oncologists.

Long-term survival in small cell lung carcinoma.

We assessed outcome in 208 patients with small cell lung carcinoma two to seven years after treatment with combination chemotherapy, with or without chest and cranial radiotherapy. Fourteen patients (6.7%) survived cancer free for 30 months or longer. Nine of these (64%) had limited disease at diagnosis and four others had extensive disease with only one metastatic site. Two patients remain alive and disease free more than five years after diagnosis but median survival is still only 3.2 years. One patient died from intercurrent causes at 5.4 years but was free from small cell lung carcinoma at autopsy. Six patients are alive and disease free at intervals greater than 30 months but less than five years from diagnosis. All surviving patients are fully active with lifestyles similar to that prior to diagnosis. Five patients died from small cell lung carcinoma which relapsed more than 30 months after diagnosis. A few patients with small cell lung carcinoma are cured but 30-month survival is insufficient to show cure as late relapses do occur. Late toxicity from aggressive therapy does not appear to outweigh the benefits of long-term survival and potential cure in small cell lung carcinoma.

Chlorambucil allergy--a series of three cases.

Three cases of chlorambucil-related skin eruption in patients with low-grade non-Hodgkin's lymphoma are described. Cases were confirmed by exclusion of other drugs, rechallenge, skin testing and histology. One patient died due to florid erythema multiforme. Only two other adequately documented cases are described.

Identification of a multidrug resistance associated antigen (P-glycoprotein) in normal human tissues.

The multidrug resistance (NDR) phenotype describes a pattern of cross-resistance to unrelated compounds observed in mammalian cell lines selected in vitro for resistance to a single agent. Overexpression of a 170,000 dalton cell membrane glycoprotein (P-glycoprotein) is associated consistently with this phenotype in these cell lines. Recently, several human tumours have been shown to contain P-glycoprotein and expression was greatest in tumours exhibiting clinical drug resistance. To explore further the significance of P-glycoprotein, we examined normal human tissues obtained at autopsy by polyacrylamide gel electrophoresis and immunoblotting using a monoclonal antibody directed against P-glycoprotein. We showed expression of P-glycoprotein in normal liver and small bowel mucosa but not in other organs examined. This suggests there may be significant expression of P-glycoprotein in certain normal human tissues and any plan to exploit P-glycoprotein clinically must take these findings into account.

Single agent etoposide in gestational trophoblastic tumours. Experience at Charing Cross Hospital 1978-1987.

Two hundred and two patients with gestational trophoblastic tumours (GTT) were treated using single agent etoposide. Patients were divided into low, medium and high risk groups using a prognostic index. Initial chemotherapy commenced with etoposide in 101 patients and 94 were accessible. Partial response (PR), defined by a log fall in serum human chorionic gonadotrophin (hCG) concentration within 1 week, occurred in 63 patients (67%) and was more common among low (5/8; 63%) and medium risk (47/64; 73%) than high risk patients (11/22; 50%) although these differences were not significant (P greater than 0.05). No patient showed a sustained rise in hCG level after etoposide and 91 (97%) showed some decrease. Ninety-one (97%) of these patients remain alive and well with median follow-up of 63 months but 29 (31%) required more intensive combination therapy. Of three deaths, two were due to progressive disease and drug resistance. Among 101 patients who had received previous chemotherapy when etoposide was first administered, response to etoposide was accessible in 39. Of these, PR occurred in 18 (46%) and only one patient progressed after etoposide. With a median follow-up of 35 months, survival in this group is 92% (36/39). All deaths were due to progressive disease and drug resistance. Single agent etoposide is very active in GTT but should be used in combination chemotherapy for patients presenting with adverse prognostic factors.

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.

Bone disease in testicular and extragonadal germ cell tumours.

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.