Carbon monoxide diffusing capacity is a poor predictor of clinically significant bleomycin lung. New Zealand Clinical Oncology Group.

In a retrospective analysis, serial lung function tests from 81 patients receiving bleomycin were studied to determine the accuracy of carbon monoxide diffusing capacity (DLCO) as a predictor of clinically significant bleomycin lung. Six of 81 patients developed clinically significant bleomycin lung, and the DLCO predicted its development in only one patient (sensitivity, one of six patients; 16.7%). Respiratory symptoms and chest x-ray abnormalities were the earliest manifestations in the other five patients. Seventy-five of 81 patients did not develop clinically significant bleomycin lung, and 12 of these had major falls (greater than or equal to 35% pretreatment level) in DLCO (specificity, 63 of 75 patients; 84.0%). In eight patients, bleomycin was continued after a major fall in DLCO, and none developed clinically significant lung toxicity. In this study, the DLCO failed to predict the development of serious bleomycin lung toxicity in all but one case. Furthermore, in some patients, it would appear that bleomycin may be stopped inappropriately after low DLCO measurements. It is important to monitor for respiratory symptoms and chest x-ray abnormalities during bleomycin treatment as these will be the earliest signs of lung toxicity in most cases.

A randomized comparison of single-agent doxorubicin and epirubicin as first-line cytotoxic therapy in advanced breast cancer.

One hundred forty-one patients with advanced breast cancer who had not received prior chemotherapy were randomly assigned to receive doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 every 3 weeks. These doses were selected to produce equivalent toxicities. All patients were assessed for toxicity, and 138 patients were assessable for response. After a median of five treatment cycles, 47% (32 of 68) of doxorubicin-treated patients achieved a partial or complete response. Response duration and survival were 10 and 12 months for doxorubicin and 8 and 10 months for epirubicin, respectively. Noncardiac toxicities were similar for both drugs. Of 41 patients receiving doxorubicin who had serial left ventricular ejection fraction assessments, seven sustained a fall of 10% or more, and one patient developed congestive cardiac failure at a cumulative doxorubicin dose of 489 mg/m2. Of 39 patients receiving epirubicin who had serial cardiac assessments, five sustained left ventricular ejection fraction falls of 10% or more and two patients developed congestive cardiac failure at cumulative doses of 178 mg/m2 and 833 mg/m2. These data indicate that an epirubicin dose of 90 mg/m2 produces toxicity equivalent to doxorubicin 60 mg/m2 but does not improve response rates, response duration, or survival in advanced breast cancer.

Proliferation kinetics of streptozotocin-induced renal tumours in mice.

Renal tumours were induced in female mice 132 days after intravenous administration of streptozotocin. The tumours exhibited papillary and/or solid architecture with papillary tumours showing no histological evidence of malignancy. Malignant behaviour, manifest as infiltration of adjacent renal tissue and lymphatic infiltration, was noted for tumours with solid architecture. Intermediate architectural forms exhibiting dual papillary and solid architecture were identified. Proliferation kinetics were evaluated by enumeration of silver-staining nucleolar organizer regions and proliferating cell nuclear antigen expression. The results showed a stepwise progress in cell proliferation between histologically normal renal tubule epithelium [untreated animals, mean AgNOR score (MAS) 2.32, mean PCNA index (MPI) 0.53%; treated animals, MAS, 2.44; MPI 0.99%], dysplastic tubule epithelium (MAS, 4.15; MPI 1.65%), papillary tumours (MAS, 5.90; MPI 3.89%) and solid tumours (MAS, 6.94; MPI, 6.80%). Solid tumours as a group were significantly larger than papillary tumours and were associated with a significantly longer mean post-injection survival interval. The findings suggest that at least some solid tumours evolve from tumours exhibiting papillary architecture.

Histopathology of the lung after bone marrow transplantation.

The histopathological changes in the lungs of 32 patients who died after bone marrow transplantation for leukaemia have been studied and compared with those found in 21 patients treated by conventional chemotherapy. The transplanted patients exhibited a higher incidence of interstitial pneumonitis, vascular lesions and viral infections, particularly cytomegalovirus (CMV), although bacterial and fungal diseases were commoner in the non-grafted subjects. The pathogenesis of interstitial pneumonitis is discussed with specific reference to the possible roles of irradiation, chemotherapy, viruses and the immunosuppressive drug cyclosporin A. Ten patients died of a syndrome characterised clinically by fever, skin rash, fluid retention, uraemia, low serum albumin concentrations, low central venous pressure and acute pulmonary oedema. These patients exhibited intra-alveolar haemorrhagic fibrinous exudation with or without interstitial changes. The aetiology of this syndrome is not known but it occurs more frequently in recipients of mismatched grafts and evidence is presented suggesting that viruses may play a significant causative role. No lesion was identified that could be directly attributed to Graft-versus-Host disease.

A phase II clinical study of mAMSA in small cell carcinoma of the lung.

Thirteen patients with small cell carcinoma of the bronchus that had become resistant to conventional chemotherapy were given 4'-(9-acridinylamino)methanesulphon-m-anisidide (mAMSA) at a dose of 90 or 120 mg/m2 at 3-week intervals. Twenty percent of the courses at 90 mg/m2 produced marked myelosuppression. No responses were observed. Median survival from the start of treatment with mAMSA was 5 weeks.

High dose melphalan with autologous marrow rescue in cancer treatment.

Autologous bone marrow rescue circumvents the major toxicity of most cancer chemotherapeutic agents. Melphalan is a particularly well suited agent for use with autologous bone marrow rescue and produces response in chemo-resistant tumours. Thirteen patients have been treated with high dose melphalan with autologous bone marrow rescue in this department. The aims of treatment were palliation, debulking of non-resectable tumours and curative adjuvant therapy. Three patients died of melphalan related toxicity. Of the remaining ten patients there were five partial remissions, one objective response, one complete remission, one with no response and two patients in whom the response is not yet assessable (adjuvant therapy). In our experience high dose melphalan is an effective means of killing tumour cells which are not sensitive to chemotherapy at conventional doses. It is recommended in young patients who have not had extensive previous radio- or chemotherapy, in the early stages of disease, with cure or prolonged remission the aim. High dose melphalan is not recommended in the older patient or in those with massive diseases and is no longer used with palliative intent.

Quantitative high-performance liquid chromatography of nucleosides and bases in human plasma.

A reversed-phase high-performance liquid chromatographic (HPLC) method has been developed for the estimation of purines, pyrimidines and their congeners in biological fluids. An initial HPLC separation allowed the collection of a number of effluent fractions, each of which contained a single component of interest. The re-application of these fractions to a second HPLC separation permitted the resolution and quantification of nanogram amounts of these components. Isocratic elution with volatile buffers renders the samples amenable to automatic sampling procedures or lyophilisation. Data are presented on the application of the method to the analysis of nucleosides and bases in human plasma.

Metastatic astrocytoma.

Two women, treated with surgery and radiotherapy for cerebral astrocytoma, developed metastases. In one case a metastasis in a craniotomy scar was probably implanted at the time of surgery; at first this was sensitive to chemotherapy and radiotherapy, but it later recurred and became resistant to treatment, with resistant tumour spreading extensively through the scalp and the cervical lymphatic chain. In the other case tumour disseminated hematogenously to the bone marrow. Both patients died of metastatic disease with primary tumours apparently well controlled. The syndrome of metastatic astrocytoma may be under-diagnosed.

Five years' experience with ChlVPP: effective low-toxicity combination chemotherapy for Hodgkin's disease.

Since 1975, 191 patients with Hodgkin's disease have been treated with a combination of chlorambucil, vinblastine, procarbazine and prednisolone (ChlVPP). Complete remission rates were 73% for previously untreated patients, 91% for patients previously treated with radiotherapy and 55% for patients previously treated with chemotherapy. In 59 patients with advanced disease who received no other treatment, a 5-year survival rate of 66% was comparable with that achieved by more toxic mustine-containing combinations. ChlVPP has few side effects, is easily given to outpatients, and can be combined with elective radiotherapy in selected patients.

Results of the surveillance policy of stage I non-seminomatous germ cell testicular tumours.

A series of 115 patients with clinical Stage I non-seminomatous germ cell testicular tumours were managed with orchiectomy and close surveillance (median follow-up 36 months, range 3-119); 34 (29.5%) relapsed, 21 within 6 months, 29 within a year and the latest at 28 months. At relapse all patients were treated with platinum or analogue-based drug combinations, supplemented in 7 by retroperitoneal node dissection; 30 patients achieved durable remissions and 2 have had further relapses successfully treated. Two died; both had malignant teratoma intermediate with primary stage T1 and vascular and/or lymphatic invasion of primary tumour. At a median follow-up time of 36 months, the survivors (98.3%) demonstrate no evidence of disease, these results matching the outcome of other methods of management. Vascular and/or lymphatic invasion was associated with an enhanced relapse rate but specific histology, T stage of the primary and pre-orchiectomy serum alpha-fetoprotein status did not appear to favour relapse. The first sign of relapse was tumour marker alone in 10 patients, radiological features alone in 12, or both in 10 patients. However, in 2 cases the relapse was first detected clinically. Furthermore, pre-orchiectomy and relapse marker status did not correlate well. These points emphasise the importance of all aspects of follow-up, none of which can be safely omitted.

Methotrexate with thymidine, inosine, and allopurinol rescue: a phase I clinical study.

A phase I clinical study of a combination of thymidine (TdR), inosine (IR), and allopurinol used as rescue from 24-hour infusions of methotrexate (MTX) was undertaken following animal studies that had shown a better preservation of antitumor activity with this system than with folinic acid. TdR and IR were given in the dose ratio 5:1 by weight throughout. Rescue from MTX, 400 mg/m2, could be achieved with a TdR dose in the combination of 1 g/m2/24 hours. This same rescue was also effective when the MTX dose was increased to 800 mg/m2, but only partly effective at an MTX dose of 1.5 g/m2. It was not necessary to raise the levels of circulating nucleosides significantly above normal to achieve rescue. MTX-related skin lesions occurred more frequently than might be expected with the MTX dose used.

Combination chemotherapy of metastatic breast cancer with vincristine adriamycin and prednisolone.

Fifty patients with metastatic breast cancer were treated with a combination of vincristine, Adriamycin and prednisolone (VAP) at four weekly intervals. Response rates of 78% for soft tissue disease, 66% for parenchymal lung disease, 67% for liver disease, and 64% for pleural effusions were seen. Only 26% of patients with bone metastases showed an objective response. These figures are as good as any previously reported for chemotherapy of breast cancer.

Late results of surveillance of clinical stage I nonseminoma germ cell testicular tumours: 17 years' experience in a national study in New Zealand.

OBJECTIVE: To re-evaluate a national prospective study in New Zealand after 17 years to define whether orchidectomy alone and surveillance for nonseminoma germ cell testicular tumour (NSGCTT) is a sound policy and matches the results achieved by other treatment protocols. PATIENTS AND METHODS: Between 1980 and 1997, 248 men with stage I NSGCTT, from six New Zealand centres, were managed by orchidectomy alone and surveillance, with treatment of relapses using combination chemotherapy. RESULTS: Seventy of the 248 patients (28%) relapsed; 42 of 92 (46%) with vascular and/or lymphatic invasion (VLI) in the primary tumour relapsed, whereas only 26 of 151 (17%) without this feature relapsed (P<0.001). VLI was the only identifiable risk factor for relapse in this series. Only one relapse occurred >28 months after orchidectomy. Despite poor compliance in some patients (12%) their survival was not prejudiced. Three patients died from disease despite chemotherapy at relapse. At 17 years and a median follow-up of 53 months, 242 of the 248 men are disease-free and the disease-specific survival rate is 98%. CONCLUSIONS: This study shows that orchidectomy alone and treatment of relapses produces excellent long-term results without the adverse effects associated with retroperitoneal node dissection or elective chemotherapy for high-risk cases.

Mismatched family donors for bone-marrow transplantation as treatment for acute leukaemia.

35 patients were treated for acute myeloid leukaemia or acute lymphoblastic leukaemia with allogeneic bone-marrow grafts from a parent, child, or sibling who was mismatched at the major histocompatibility complex (MHC). 11 of these patients are alive at least 6 months after grafting, 5 of them after more than 2 years. Of the 15 patients aged under 20 at the time of the graft, 8 are alive and well 6 months to 3 years later. Cyclosporin A was given to all patients after grafting. 1 patient died of acute graft-versus-host disease and in 2 other cases this was a major factor in their death. Graft failure caused the death of 2 patients. 4 patients died of recurrent leukaemia. A fatal complication in 12 patients was pulmonary oedema, often associated with convulsions, intravascular haemolysis, and renal failure. Some of these patients had viral or bacterial infections, but in the majority the syndrome was not associated with demonstrable infection. This syndrome, in which the essential lesion appears to be vascular, was much more common in recipients of mismatched than matched grafts. 3 others died from lung disease in which infection was a factor.