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.

Adjuvant chemotherapy for non-metastatic osteosarcoma of the extremities in two New Zealand cancer centres.

BACKGROUND: Adjuvant chemotherapy significantly improves survival of patients with non-metastatic osteosarcoma but most of the data come from trials conducted in major international cancer centres. AIM: To review the efficacy and toxicity of an adjuvant chemotherapy regimen used in two regional cancer centres in New Zealand. METHODS: Retrospective review of patients treated for non-metastatic high-grade osteosarcoma of the extremities. The regimen (POMA) consists of high-dose-methotrexate 8 g/m2 and vincristine 1.5 mg/m2 (maximum 2 mg) on days 1 and 8 followed by folinic acid then doxorubicin 50 mg/m2 and cisplatin 100 mg/m2 on day 15. This cycle was repeated every 35 days. Following amputation patients received six cycles while in selected patients two cycles were planned prior to limb salvage surgery followed by a further four cycles. Actuarial survival was calculated using the Kaplan-Meier method. RESULTS: Twenty patients were treated with POMA between 1986 and 1993. Amputation was performed in 16 patients and limb-salvage surgery in four. Sixteen patients (80%) remain alive with no evidence of disease at a median follow-up of 40 months. Thirteen patients (65%) have been continuously disease-free. Actuarial survival at five years is 70%. Seven patients relapsed, six in lungs, of whom four underwent pulmonary metastasectomy; three of these remain free of disease 31, 35 and 40 months later. There was no local relapse. The toxicity of POMA is significant but tolerable. CONCLUSION: The results obtained at two regional cancer centres in New Zealand using POMA compare favourably to those achieved in clinical trials performed at major international cancer centres.

Carboplatin and chlorambucil combination chemotherapy as treatment for patients with ovarian cancer.

Fifty-six patients with ovarian cancer (three stage IC, nine stage II, 33 stage III and II stage IV) were treated with carboplatin 350 mg m-2 i.v. day 1 and chlorambucil orally 0.15 mg kgm-1 days 1-7 inclusive, repeated every 28 days for eight courses. The regimen was well tolerated and was virtually free of nephro- and neurotoxicity. Grade III or IV hematology toxicity occurred in 18 patients but only 31 or 330 courses administered were delayed. Of 40 assessable patients eight achieved a clinical/radiologic complete response and 17 a clinical/radiologic partial response. Actuarial survival at 50 months was 65% for stage II patients, 27% for stage III patients and no stage IV patients survived beyond 20 months. Forty-two per cent of patients with residual disease less 2 cm survived 50 months, compared with 44% of patients with moderate volume (2-5 cm) residual disease and 6% of patients with bulk residual disease. This is an active, well tolerated regimen. However, only patients with small volume residual disease have a significant chance of prolonged survival.

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.

Ondansetron reduces chemotherapy induced nausea and vomiting refractory to standard antiemetics.

Ondansetron, a selective 5HT3 (serotonin) antagonist, was used in patients refractory to standard antiemetics. Seventy-five patients receiving chemotherapy without cisplatin were given ondansetron 4 mg IV and 4 mg orally immediately prior to chemotherapy, then 8 mg orally after six and 12 hours, followed by 8 mg orally eight hourly during days 2-5. Complete control of vomiting occurred in 52 patients (69%) on the first day and 45 patients (60%) on days 2-5. Sixty patients (80%) preferred ondansetron to their previous antiemetics. The efficacy of ondansetron was maintained over multiple chemotherapy cycles. Ondansetron was also given to 16 patients receiving cisplatin chemotherapy. They received 8 mg IV immediately prior to chemotherapy followed by an infusion of 1 mg/hr for 8 hr, with 8 mg orally at the end of the infusion and then 8 mg orally eight hourly during days 2-6. Some control of vomiting (less than = 5 vomits) was achieved in eight patients (50%) on the first day and in 14 patients (87%) on subsequent days. Eight patients (50%) preferred ondansetron to their previous antiemetics. Adverse events with ondansetron were frequent but mild, with constipation and headache being most common. Ondansetron is highly effective in patients refractory to standard antiemetics, especially after noncisplatin chemotherapy.

A clinical study of nafazatrom in advanced human breast cancer.

Prostaglandins (PGs) have been shown to inhibit tumour metastases in experimental animal systems. Nafazatrom is a pyrazolinone derivative that increases endogenous prostacyclin (PGI2) and has experimental anti-cancer activity. In the present study, nafazatrom was given to 47 women with advanced breast cancer; objective remission of metastases was seen in 2 patients and stabilisation of disease in 1 case. Nafazatrom was safe and well tolerated.

ChlVPP combination chemotherapy for Hodgkin's disease: long-term results.

Two hundred and eighty-four patients with advanced Hodgkin's disease (HD) (stage II with poor prognostic features and stage III/IV) have been treated with the ChlVPP combination chemotherapy regimen (chlorambucil, vinblastine, procarbazine and prednisolone) in a single-centre unselected series. Median follow up is 92 months. Fifty-five patients had previously received radiotherapy but none had received previous chemotherapy. Eighty-five per cent of previously untreated patients and 91% of previously irradiated patients entered complete remission (CR); 71% and 68% of these respectively remain in CR at 10 years and 65% and 64% of each group respectively are alive at 10 years. On univariate analysis, age, stage, site of visceral disease and lymphocyte count predicted survival and on multivariate analysis age, absence of symptoms, absence of lung, liver or bone marrow disease and achieving a CR remained important predictors of survival. Acute toxicity was mild. The 10 year actuarial risk of acute leukaemia was 2.7%. This study adds further support to the view that chlorambucil is as effective and less toxic than mustine in combination chemotherapy for HD. We suggest that MOPP chemotherapy is no longer routinely indicated for HD.

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.

Carboplatin, etoposide, and ifosfamide as intensive chemotherapy for small-cell lung cancer.

Thirty-two previously untreated, fit patients with small-cell lung carcinoma (SCLC) were treated with an intensive combination chemotherapy regimen, with the aim of prolonging survival, as follows: carboplatin 400 mg/m2 intravenously (IV) day 1, ifosfamide 5 g/m2 IV day 1 in a 24-hour infusion with mesna, and etoposide 100 mg/m2 IV days 1 to 3, repeating at 28-day intervals for six courses. Limited-disease (LD) patients were given concurrent hyperfractionated radiotherapy for the first two courses, and all patients achieving a complete remission (CR) were offered prophylactic cranial irradiation (PCI). For 18 LD patients, the overall response was 94% with 72% CRs. For 14 extensive-disease (ED) patients the overall response was 100% with 29% CRs. Median response duration for LD patients was 11.5 months and for ED patients 7.5 months. Median survival for LD patients was 19 months with a predicted 24% 2-year survival and for ED patients 9.5 months with a predicted 14% 2-year survival. Hematologic toxicity was severe with 100% developing World Health Organization (WHO) grade 3-4 neutropenia and 94% WHO grade 3-4 thrombocytopenia during treatment. Seventy-two percent of patients required a dose reduction at some stage during treatment because of neutropenic infection or thrombocytopenia requiring platelet transfusions. Despite very high response rates, this intensive regimen achieves survival results only modestly better, if at all, than those reported for less toxic conventional regimens.

High dose melphalan, BCNU and etoposide with autologous bone marrow transplantation for Hodgkin's disease.

Thirty-eight patients with previously treated Hodgkin's disease were given high dose combination chemotherapy using melphalan and BCNU and autologous bone marrow transplantation. In 25 patients etoposide was added in conventional dosage. During the course of the study the dose of melphalan was increased from 80 to 140 mg m-2 and the dose of BCNU from 300 to 600 mg m-2. The response rate was 76% with 53% complete remission. Forty-five per cent of the patients are free of disease at 4-20 months follow-up. There were eight (26%) treatment-related deaths due to lung damage (seven cases) and irreversible cardiac failure (one case). Fatal lung damage occurred only in patients receiving 600 mg m-2 of BCNU with high dose melphalan. The dose of BCNU given with high dose melphalan should not exceed 500 mg m-2. This treatment is effective against relapsed Hodgkin's disease but must be used cautiously. The best time for its use remains to be determined.

Treatment of relapsed and refractory acute leukaemia with high-dose cytosine arabinoside and etoposide.

A total of 65 patients under the age of 55 with acute leukaemia received high-dose cytosine arabinoside (Ara-C) in combination with high-dose etoposide without an anthracycline. Complete remission rates for patients with relapsed or refractory acute myelogenous leukaemia (AML) were 15/25 (60%) and 11/16 (69%), respectively. The complete remission rate for patients with refractory or relapsed acute lymphoblastic leukaemia (ALL) was 10/18 (56%). The treatment-related mortality was 17%. Nine patients whose leukaemia relapsed after matched allogeneic, sibling bone-marrow transplantation (BMT) were also treated in this way; the treatment-related mortality in this group was high (7/9) and the duration of remission in the two patients who responded, too short to justify this intensive treatment in such patients. Similarly, patients who underwent BMT after achieving a complete remission with high-dose Ara-C and etoposide did very poorly, only one patient surviving well and disease-free at 8 months. The important finding in this study was the high complete remission rate rapidly obtained in patients with relapsed or refractory AML without using an anthracycline.

Infused vincristine and adriamycin with high dose methylprednisolone (VAMP) in advanced previously treated multiple myeloma patients.

Forty-five patients with relapsed or refractory multiple myeloma received continuous infusions of vincristine (0.4 mg total dose daily for 4 days) and adriamycin (9 mg m-2 daily for 4 days) with a high dose of methylprednisolone (1 g m-2 i.v. or p.o. daily by 1 h infusion), the VAMP regimen. Sixteen (36%) responded, with a median duration of remission of 11 months and median survival of 20 months. Major toxicities encountered were infective and cardiovascular. Two smaller groups of myeloma patients were treated with high dose methylprednisolone (HDMP) alone, or VAMP plus weekly low dose cyclophosphamide (Cyclo-VAMP). HDMP produced short responses in 25% of patients with less toxicity than VAMP. Cyclo-VAMP was used in a highly selected group of patients who had previously responded to high dose melphalan. It was well tolerated and produced responses in 61% of this group.

Melphalan and total body irradiation (TBI) versus cyclophosphamide and TBI as conditioning for allogeneic matched sibling bone marrow transplants for acute myeloblastic leukaemia in first remission.

Between June 1981 and April 1986 63 patients with acute myeloid leukaemia (AML) in first remission and HLA-identical sibling donors were entered into a prospective study comparing cyclophosphamide (CY) + total body irradiation (TBI) with melphalan + TBI as conditioning therapy prior to transplantation. Thirty-six patients received CY/TBI and 27 received melphalan/TBI. The actuarial probability of remaining in remission for patients receiving melphalan/TBI was 94% compared with 66% following CY/TBI (p greater than 0.01). By including a comparable group of 41 patients with AML in first remission, conditioned with CY/TBI prior to the onset of the study, the greater anti-leukaemic effect of melphalan/TBI compared to CY/TBI was unchanged and statistically the chance of this being wrong is 1 in 10 (p less than 0.1). The overall survival in remission of both arms of the study was the same with 15/27 patients (55%) surviving in remission following melphalan/TBI compared with 19/36 patients (53%) following CY/TBI. The benefit obtained in reduced relapse was offset by the combined nephrotoxic effect of melphalan and cyclosporin which was not identified until the programme had been underway for a period of time. This shows that misinterpretation of 'no survival advantage' for the new treatment may occur due to unforeseen and preventable toxicities.