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Aim: Trastuzumab can induce cardiotoxicity, particularly when combined with anthracyclines. Myocardial human epidermal growth factor receptor 2 (HER2) expression may be transiently upregulated by a compensatory mechanism following cardiac stress. 111In-DTPA-trastuzumab, scintigraphy can detect HER2 positive tumour lesions, however previously, we found myocardial uptake in only 1 of the 15 anthracycline-pre-treated patients with a median of 11 months after the last anthracycline administration. To evaluate whether myocardial HER2 expression is upregulated by anthracycline-induced cardiac stress or in case of heart failure by chronic pressure or volume overload, we performed 111In-DTPA-trastuzumab scans in patients shortly after anthracyclines and with non-anthracycline-related heart failure., Methods: Patients within 3 weeks after undergoing 4-6 cycles first-line anthracycline-based chemotherapy and patients with heart failure due to cardiac disease underwent gammacamera imaging 48 and 96 h after 111In-DTPA-trastuzumab intravenously., Results: Myocardial 111In-DTPA-trastuzumab uptake was observed in 5 out of 10 anthracycline-treated patients, who all were without symptomatic cardiac dysfunction. None of the 10 heart failure patients showed myocardial uptake., Conclusion: Shortly after completion of anthracycline treatment, myocardial HER2 over-expression was detectable in 50% of the patients. 111In-DTPA-trastuzumab scintigraphy after anthracyclines prior to adjuvant trastuzumab potentially identifies patients susceptible for trastuzumab-related cardiotoxicity and thus may facilitate the optimal timing of trastuzumab therapy.

Background: A testicular germ cell tumour (TGCT) predisposing gene has been mapped to the Xq27 region on the X chromosome. These linkage findings remain to be confirmed by other studies., Methods: In 276 patients and 169 unaffected first-degree male relatives, 12 microsatellite markers covering the candidate region were genotyped and used to study possible association of TGCT with Xq27., Results: In contrast to previously reported linkage of familial TGCT and cryptorchidism with Xq27, we observed an association between the subset of TGCT cases without a family history of TGCT or cryptorchism and marker DXS1193 (p=0.014). Carriers of minor alleles were at increased risk (odds ratio (OR) 4.7, confidence interval (CI) 1.1-19.6), Conclusion: We found an association on Xq27 in a subset of TGCT cases, which suggests the presence of an X-linked gene that slightly or moderately increases risk to develop sporadic TGCT but not cryptorchidism.

The drug-efflux pumps P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) are present in the blood-testis barrier (BTB) and may hamper the delivery of cytotoxic drugs to the testis. The precise localisation of P-gp and MRP1 in testicular tissue and the presence of the efflux pumps MRP2 and breast cancer resistance protein (BCRP) in the BTB are unknown. We therefore studied the localisation of these pumps in the BTB in normal testis (n = 12), in non-seminoma (n = 10) seminoma (n = 10), and testicular lymphoma (n = 9). Slides were scored semi-quantitatively for P-gp, MRP1, MRP2 and BCRP and blood vessels with factor VIII antibody. In normal testis, P-gp and BCRP were strongly expressed by myoid cells and luminal capillary endothelial wall and P-gp also by Leydig cells. MRP1 was observed at the basal side of Sertoli cells and on Leydig cells. MRP2 was only weakly expressed by myoid cells. Seminomas and non-seminomas expressed P-gp and/or BCRP and/or MRP1, lymphomas strongly expressed P-gp, weakly expressed BCRP and did not or showed weak expression of MRP1. There was very little staining for MRP2 in the tumours. Newly formed vessels in all tumours only expressed P-gp and BCRP. P-gp, BCRP and MRP1 are present in different cell layers of the normal testis, suggesting the optimal protection of spermatogenesis. In germ cell tumours, this expression pattern may explain the chemoresistance observed to P-gp, BCRP and MRP1 substrates. In germ cell tumours and testicular lymphomas, P-gp and BCRP expression by tumour cells and by newly formed vessels may also contribute to chemoresistance. These findings underscore the importance of removing the affected testis in cases of primary germ cell tumours and testicular lymphomas, irrespective of whether the patient has already undergone chemotherapy.

The aim of this study was to gain insight into the quality of life (QoL) and stress response of female spouses of men cured of testicular cancer in the long-term. Time since treatment completion varied from 0.5 to 23.8 years. Two hundred and fifty nine testicular cancer survivors and their spouses completed the Dutch version of the MOS Short Form (SF)-36 and the Impact of Event Scale. QoL data from a reference group of women were used for comparison. Spouses who had relationship with the testicular cancer survivor before the diagnosis (spouses during testicular cancer) had better functioning scores than the reference group, especially with respect to the physical QoL domains. Spouses who had started a relationship after treatment (spouses after testicular cancer) experienced more problems with psychological QoL domains than spouses during testicular cancer and than the reference group. The stress response of spouses during testicular cancer was related to that of the testicular cancer survivors and to the extent of treatment they had received. Although stress response levels were low, spouses during testicular cancer reported more stress response than the testicular cancer survivors. Time since completion of treatment did not affect QoL or stress response. This study showed that spouses during testicular cancer had a good QoL and little stress response. Functioning of spouses after testicular cancer was poorer with respect to various QoL domains, particularly the psychological measures.

Enlarged mediastinal lymph nodes in patients with previous extrathoracic malignancy require pathological verification. However, surgical procedures lead to morbidity and (rarely) mortality. Endoscopic ultrasound with fine-needle aspiration (EUS-FNA) is a minimally invasive, outpatient procedure. We prospectively assessed its usefulness in patients with mediastinal abnormalities and previous extrathoracic malignancy. All patients underwent EUS-FNA prior to planned surgical procedures. Specimens were categorised as positive, negative, or inconclusive. Surgical procedures were cancelled after positive EUS-FNA. Twenty patients underwent EUS-FNA, being positive in eleven and providing an alternative diagnosis in one patient (a total of 60%). In 8 patients, EUS-FNA was negative or inconclusive, while surgery was positive in five and negative in three. Sensitivity and specificity of EUS-FNA were 69 and 100%, respectively. EUS-FNA is useful in the assessment of mediastinal abnormalities in patients with previous extrathoracic malignancy. Surgical diagnostic procedures were precluded in 60% of such patients.

Testicular cancer patients have an increased risk for coronary artery disease more than ten years after cisplatin-based chemotherapy. We investigated whether vascular changes, including endothelial dysfunction, are present earlier. Ninety chemotherapy-treated testicular cancer patients (median follow-up of seven years) were compared with 44 patients after orchidectomy only and 47 healthy men. Microalbuminuria was present in 10 (12%) chemotherapy patients, one stage I patient and none of the controls. Chemotherapy patients had higher levels of fibrinogen, C-reactive protein (hs-CRP), von Willebrand factor (vWF), plasminogen activator inhibitor (PAI-1), and tissue-type plasminogen activator (t-PA). Chemotherapy patients with elevated PAI-1 (25/90) showed clustering of cardiovascular risk factors resembling the metabolic syndrome. In conclusion, cured testicular cancer patients showed a high prevalence of microalbuminuria and increased plasma levels of endothelial and inflammatory marker proteins, which might progress to more severe endothelial dysfunction and overt atherosclerosis.

Familial occurrence of testicular cancer suggests a genetic predisposition to the disease. A genetic susceptibility may also be reflected by the occurrence of bilateral testicular neoplasms and the high rates of urogenital developmental anomalies in families prone to testicular cancer. In this study, the proportion of familial testicular cancer cases was analyzed retrospectively in a single-centre population of 693 testicular cancer patients treated between 1977 and 1997 and the relative risk (RR) for first-degree relatives of patients was estimated. In addition, the existence of bilateral testicular neoplasms and urogenital developmental anomalies in familial testicular cancer patients was evaluated. 24 of the 693 patients (3.5%) had a first-degree relative with testicular cancer. These 24 cases belonged to 17 families; in 7 of these 17 families both affected first-degree family members were part of the study population of 693 patients. Consequently, the 693 studied patients belonged to a total of 686 families. Thus, the actual proportion of familial testicular cancer was 2.5% (17 of 686 families). The familial cases consisted of 11 brother pairs, including 2 pairs of identical twins and 1 pair which also had two affected cousins, and 6 father-son pairs (in total 36 cases, 12 treated elsewhere). Estimates of the RR to first-degree relatives showed a 9- to 13-fold increased RR to brothers (P < 0.001) and a 2-fold increased RR to fathers (P = non-significant (n.s)) of testicular cancer patients. Among the 36 patients with familial testicular cancer, 2 (5.6%) had bilateral testicular cancer, 4 (11.1%) had undescended testis, 3 (8.3%) had inguinal hernia, and 1 (2.8%) showed renal hypoplasia. The present data on familial occurrence of testicular cancer may lend support to a role of genetic factors in the aetiology of testicular cancer.

Development of second testicular tumours, i.e. bilateral testicular cancer, is influenced by systemic chemotherapy for the first tumour. The prevalence of bilateral testicular cancer was studied in patients with initial stage I disease, in which no systemic treatment was given after orchidectomy. All stage I testicular cancer patients entered a surveillance study with an intensive follow-up since 1982. We hypothesised that after 1982, bilateral testicular cancer was diagnosed at an earlier stage of disease. The prevalence of bilateral testicular cancer was 4.7% (8/170) in stage I patients treated between 1967 and 1981, and 2.9% (8/275) in stage I patients treated between 1982 and 1997 (P > 0.5 chi 2-test). In the period 1967-1981, 6 patients had stage I second tumours and 2 patients had stage III second tumours. The former 6 patients are alive with no evidence of disease and the 2 patients with metastatic tumours died of disease or treatment. In the period 1982-1977, all 8 patients had stage I second tumours and all are alive with no evidence of disease. The overall prevalence of bilateral testicular cancer in stage I patients was 3.6% and has slightly decreased over the past three decades. Intensive follow-up, improvement of radiodiagnostic computed tomography techniques, availability of serum tumour markers, and patient education have resulted in earlier diagnosis and lower stage of contralateral testicular tumours, contributing to improved prognosis.

A European Conference on Continuing Medical Education (CME) in Oncology was designed and organised in Dublin (Ireland), on 12th and 13th October 1995 by the European School of Oncology in collaboration with University College Dublin and with the financial support of the European Commission (Europe Against Cancer Programme). Two experts were invited from each Member State and all attended the Conference with the sole exception of the representatives of Luxembourg, who did not attend due to unexpected important commitments. Observers were invited to contribute to the discussion as representatives of organisations that were involved either directly or indirectly in CME. The Conference took the format of a plenary session coupled with the identification of five discussion groups formed to debate key areas in CME at a European level in oncology (Table 1). As a result of these discussions and subsequent consultations, an agreement was reached on the following statements: (a) Continuing Medical Education (CME) is an ethical duty and an individual responsibility for each doctor. Although CME should remain voluntary at the present time, it is nevertheless a professional obligation since almost 50% of medical knowledge becomes obsolete after ten years. It should be organised with clear guidelines for medical personnel working in hospitals, in primary health care and in private practice. (b) The CME system within the European Union (EU) should remain self-directed without the necessity for interval examinations: it should be interdisciplinary and must be driven and controlled by the profession itself. (c) A common concept and system within a CME framework may have a considerable impact on EU integration. It should certainly be developed, maintained and monitored at national level but on the basis of a common European model to ensure scientific and cultural interchange among Member States. (d) It was agree that a credit system is needed to help doctors keep track of their CME activities: the system should be based on the accumulation of credit points (one credit equalling one hour of continuing medical education) and monitored at a national level. Credit transfer among Member States is vital to facilitate exchange between Member States. (e) Oncology provides a very useful model of CME within which guidelines can be proposed and tested. Harmonisation of CME systems among the different European cancer organisations and scientific societies within this model system may represent a useful basis that other specialities can follow.

The efficacy and toxicity of intraperitoneal (i.p.) cisplatin plus systemic etoposide were studied in 36 patients with small (< 2 cm) residual i.p. ovarian cancer after achieving a partial response to platinum-based, first-line chemotherapy. Treatment comprised 90 mg/m2 i.p. cisplatin with intravenous (i.v.) sodium thiosulphate (day 1) and 600-800 mg/m2 i.v. etoposide (days 1 and 2), every 4 weeks for four to six cycles. 7 patients achieved a pathological complete response (pCR), one a pathological partial response and 16 were clinically stable without evidence of disease. After a median follow-up of 13 months, the median progression-free survival (PFS) was 11 months (95% confidence interval 7-16 months). The actuarial PFS at 24 months is 22% (95% confidence interval 8-36%). Three of six relapses after achieving a pCR (50%) were sited i.p., and 9 of 14 other patients with disease progression (64%) had an i.p. relapse, indicating insufficient local efficacy. There was no renal toxicity, but grade 3-4 leucopenia occurred in 63% and grade 3-4 thrombocytopenia in 8% of cycles, while nausea, vomiting and complete alopecia were common. Although side-effects were acceptable, the efficacy of treatment with i.p. cisplatin plus i.v. etoposide is limited.

Patients with breast cancer and a high number of involved axillary lymph nodes have a poor prognosis, despite adjuvant chemotherapy. The 5-year disease-free survival (DFS) in this group amounts to 30-40% and the 10-year DFS is only 15-20%. Therefore, new treatment modalities are being sought for this group of patients. The aim of the present study was the evaluation of the efficacy of high-dose chemotherapy combined with autologous bone marrow support. 24 patients with a primary breast cancer with more than five involved axillary lymph nodes received, after surgery, six courses of induction chemotherapy followed by ablative chemotherapy and reinfusion of autologous bone marrow. All patients were premenopausal or less than 2 years postmenopausal. Induction chemotherapy consisted of methotrexate (MTX) 1.5 g/m2 intravenous (i.v.) and 5-fluorouracil (5-FU) 1.5 g/m2 i.v. on day 1, prednisone 40 mg/m2 orally on days 2-14, doxorubicin 50 mg/m2 i.v. and vincristine 1 mg/m2 i.v. on day 14. Courses were repeated six times every 4 weeks. 10 patients received cyclophosphamide 7 g/m2 i.v. and etoposide 1.5 g/m2 i.v. as intensive regimen, in 14 patients this comprised mitoxantrone 50 mg/m2 i.v. and thiotepa 800 mg/m2 i.v. Reinfusion of autologous marrow followed on day 7. Finally, patients received locoregional radiotherapy for extranodal disease and tamoxifen 40 mg daily orally over a period of 2 years. The median age of patients was 42 years, range 29-54. The median number of involved nodes was 10. During induction therapy, fever requiring i.v. antibiotics occurred in 4% of 144 courses, 14% of patients suffered from mucositis WHO grade 2-3, and the other patients had mucositis grade 1. During the ablative chemotherapy, 1 patient died, 6 developed septicaemia, 5 showed mucositis grade 3-4 and the other patients had mucositis grade 1 or 2. In the follow-up, 1 patient died from acute cardiac failure. Reversible radiation-induced pneumonitis occurred in 7 out of 14 irradiated patients; symptoms started directly following radiotherapy and lasted for several weeks, but disappeared in due course. During follow-up, 2 patients with six and > 10 positive nodes, respectively, have relapsed after 18 and 36 months, both in the cyclophosphamide/etoposide regimen. Median observation is 3 years, disease-free survival at 5 years is predicted to be 84%. Intensive treatment in these patients with high numbers of involved axillary lymph nodes is a toxic regimen, but may improve the chance of surviving free of disease.

25 patients with residual or recurrent ovarian cancer were treated with the new platinum complex zeniplatin (CL 286,558) and 23 patients were evaluable for response. Responses were achieved in 4 patients, 1 complete and 3 partial remissions (16%). 7 patients had stable disease and 12 patients had tumour progression. At a median follow-up of 12 months, the median progression-free survival in responding patients was 11 months and overall survival 81%. The median overall survival of progressive patients amounted to 9 months, indicating the advanced stage of disease in most patients. Renal function was monitored by isotope clearance studies. There was no significant change in effective renal plasma flow (ERPF) or glomerular filtration rate (GFR) in 10 patients who completed six cycles of treatment. 1 patient with a marginal creatinine clearance at baseline suffered from sudden and severe renal failure during the first cycle. Zeniplatin may be active in relapsing, platinum-pretreated patients, and has no direct effects on renal function as measured by isotope clearance. Despite these findings, occasional nephrotoxicity may occur in patients with compromised kidney function, even with prophylactic hydration, and thus limit the application of this new analogue.

5-Fluorouracil (5-FU) activity has been improved by the use of leucovorin (LV) or alpha-2a interferon (alpha-IF). We investigated the feasibility and activity of addition of alpha-IF to a 5-FU/LV regimen. A phase I study with 26 patients (14 previously untreated, 12 previously treated) with disseminated cancer was conducted. 15 patients were treated with 5-FU/LV and 11 with 5-FU/LV/alpha-IF. The 5-FU/LV regimen consisted of escalating doses of 5-FU bolus intravenously on days 2 and 3, combined with repeated oral LV on days 1, 2 and 3. Treatment was every 2 weeks. In the 5-FU/LV/alpha-IF schedule, 18 x 10(6) U alpha-IF subcutaneously daily was added on days 1, 2 and 3. The phase I study was followed by a phase II study of 5-FU/LV/alpha-IF at the established 5-FU dose in 29 previously untreated patients with disseminated colorectal cancer. The optimal 5-FU dose in both parts of the phase I study was 750 mg/m2/day. Mucositis, diarrhea and leucopenia were dose limiting. Although alpha-IF added its own toxicity (fever, flu-like symptoms, fatigue), it did not decrease the optimal dose of 5-FU. In the phase II study 28 patients were evaluable for response: three complete responses and 12 partial responses were observed (response rate 54%, 95% confidence interval, 34 to 72%). Pharmacokinetics of oral LV was performed in patients treated with and without alpha-IF: significantly higher serum levels of LV and 5-methyltetrahydrofolate were found after alpha-IF addition. Influence of alpha-IF on gastrointestinal absorption or renal clearance could be excluded. In conclusion, this 5-FU/LV/alpha-IF combination seems active in metastatic colorectal cancer. The pharmacokinetic interaction between alpha-IF and LV may play a role in the activity of this regimen. Controlled studies are necessary to establish the value of addition of alpha-IF to 5-FU/LV regimens.

In 56 patients with disseminated or locally advanced breast cancer it was attempted to reach a state of no evidence of disease by a remission induction regime containing prednisone, 5-fluorouracil, methotrexate, doxorubicin and vincristine. If successful, patients received an intensification regimen consisting of cyclophosphamide (7 g/m2) and etoposide (1.5 g/m2) with autologous bone marrow reinfusion. The complete remission rate of the induction regimen was 52% and the partial remission rate 42%. 32 patients received the intensification regimen. Two toxic deaths occurred. The median time to disease progression in the group with disseminated disease was 15 months. After a median observation of 4 years, 11 out of 19 patients with locally advanced breast cancer were free of disease. It is concluded that this approach may lead to prolonged disease-free survival in patients with locally advanced breast cancer, but does not influence the survival in disseminated disease.

In a phase I/II study the safety, immunostimulatory and antitumor effects of a combined OKT3/interleukin 2 (IL-2) treatment was studied in 15 cancer patients who failed IL-2 treatment. OKT3 was given as a 2-h intravenous infusion. Doses of 50, 100, 200 and 400 micrograms OKT3 were studied. Within 24 h, subcutaneous IL-2 was started 5 days/week for 4 weeks, at a dose of 9-18 x 10(6) U daily. Maximum tolerated dose was 400 micrograms OKT3 with neurotoxicity as dose-limiting toxicity. Toxicity of subcutaneous IL-2 was acceptable. At the maximum tolerated dose, 9 patients with renal cell carcinoma with measurable disease were treated in a phase II setting. 8 patients were evaluable for response. 4 patients had stable disease and 4 had progressive disease. An increase of activated lymphocyte subpopulations could not be found, although OKT3 was detectable on lymphocytes in vivo. Only if laboratory studies shed light on methods of improving immunostimulating effects of OKT3 will further clinical studies be warranted.

In patients with residual ovarian cancer after standard platinum-based induction, dose intensification was achieved by intraperitoneal administration of cisplatin 90 mg/m2 with intravenous Na thiosulphate and increasing dosages of etoposide. 40 patients entered the study, 4 on 200 mg/m2, 6 on 400 mg/m2, 22 on 600 mg/m2 and 8 on 800 mg/m2 etoposide. The optimal dose for etoposide was 600 mg/m2. 29 patients on the two highest dose steps were evaluable for response. 14 patients reached a complete remission, which was surgically confirmed in 6. All these patients initially had tumour residuals smaller than 1 cm. 3 patients had a partial response, 4 had stable disease and 8 progressed. At a maximal follow-up of 2 years (median 12 months), median time to progression was 12 months and median overall survival was 14 months. Of the 14 patients with complete remission, 2 relapsed at 9 and 11 months. Apart from a rash, in 4 of 22 patients at 600 mg/m2 and in 5 of 8 at 800 mg/m2 etoposide, the main toxicity was leukopenia grade 3-4 in 58% of cycles on 600 and in 76% at 800 mg/m2 etoposide. Leukopenic fever, however, occurred only three times; thrombocytopenia was rare. Cycles had to be delayed sporadically and the etoposide dose was reduced in 9% of all cycles at 600 and in 11% at 800 mg/m2. Intraperitoneal instillation of cisplatin gave no peritoneal symptoms. Intraperitoneal cisplatin with intravenous etoposide was tolerable and effective for patients with small tumour residuals after induction for stage III ovarian cancer.

A consecutive phase I and phase II study of a 14-days continuous infusion schedule of 5-fluorouracil with weekly bolus injection leucovorin was performed in 10 and 21 patients, respectively. Chemotherapy courses were repeated every 4 weeks. 1 patient in the phase I study was pretreated, all the others had no prior chemotherapy. 300 mg/m2 continuous infusion of 5-fluorouracil for 14 days could not be combined with any dose of leucovorin 20-200 mg/m2 without severe toxicity, mainly gastrointestinal. A 5-fluorouracil dose of 200 mg/m2 day for 2 weeks, combined with weekly bolus injection of 200 mg/m2 leucovorin was found to be feasible. The phase II study was performed at this dose level. In 21 patients a response rate of 5/21 [23.8%, 95% confidence interval (CI) 8.2-47.1%] was observed, and the overall response rate was 8/29 (27.6%, 95% CI 12.7-47.2%). Responses were observed in patients with liver (4), lung (1), abdominal (1), and multiple (2) metastases. Median survival was 14.5 months. Toxicity was low, mucositis WHO grade 1-2 being most frequent (36/113 courses = 31.9%). Patients' acceptance of this continuous infusion schedule was generally good.

In a retrospective study of 35 patients with stage III-IV ovarian cancer, the probability to reach a complete (CR) or partial remission (PR) was studied by comparing the initial level, half-life and normalisation time of CA-125 during chemotherapy. In 15 CR patients, pretreatment CA-125 level was lower (70 U/l, range 16-1500 U/l) than in 20 PR patients (800 U/l, range 60-9000 U/l). The median normalisation time (NT) was 6 weeks in CR (range 0.7-5.5 months) and 4 months in PR patients (range 1.2-9 months). Marker half-life was 12 days for the CR group (range 4.5-30 days) and 21 days for the PR group (range 5.5-39 days). Remission duration (r = 0.56) and log cell kill (r = 0.72) were correlated with survival. Combining initial tumour diameter, marker level and NT predicted CR in 87.5% and PR in 86%. Estimating log cell kill by combining marker half-life and doubling time gives more insight into tumour cell kinetics and individual survival.

170 patients were treated with continuous infusion of epirubicin, mitoxantrone, carboplatin or 5-fluorouracil through an implanted venous access port with a portable infusion pump. A total of 440 cycles were given on an outpatient basis. The patients were instructed how to dissolve their drugs and to change the syringes. The complication rate was low. 10 patients developed a thrombosis of the subclavian vein, resulting in cessation of therapy in 5. Pulmonary embolism occurred twice, in 1 patient during a period of subclavian vein thrombosis. Needle dislocation occurred 6 times and catheter occlusion 20 times. Patency was restored with saline or urokinase. Local infection occurred 3 times and systemic infection only once. This technique is suitable for continuous infusion of different cytostatic drugs on an outpatient basis. Patients were able to prepare their drugs at home and the system can remain in situ for 3 weeks without increasing the complication rate.

33 patients (median age 39 years) with advanced seminoma were treated with 4 courses of alternating cisplatin-containing chemotherapy PVB/BEP (cisplatin, vinblastine and bleomycin; bleomycin, etoposide and cisplatin). Patients were classified as stage IIC (n = 7), IID (n = 9), III (n = 13) and IV (n = 4). 8 had had prior radiotherapy; 9 had an elevated beta human chorionic gonadotropin (beta HCG). 30 patients were evaluable for response and 33 for toxicity. During chemotherapy 3 patients died, 1 due to malignant disease, another due to a cardiac arrest, and 1 patient of a bleomycin pneumonitis. 13 (43%) had a complete remission and 17 (57%) had a clinical partial remission (residual radiographic mass). At a median follow-up of 28 months (range 16-88), 3 patients relapsed, 6-8 months after entry. After completion of therapy there were 2 deaths, 1 due to bleomycin pneumonitis and 1 neither tumour nor treatment related. 26 of 33 (79%) patients achieved a continuously disease-free status. Leucocytopenia and thrombocytopenia of WHO grade 3/4 occurred in, respectively, 32/33 (97%) and 20/33 (61%) of the patients. This study shows that alternating PVB/BEP in this group yields comparable response rates with non-alternating schedules but at the expense of considerable toxicity.

Serum levels of cortisol (C), androstenedione (A), dehydroepiandrosterone (D), estrone (E1) and estradiol (E2) were chosen as parameters to compare the bioavailability of megestrol acetate (MA) and medroxyprogesterone acetate (MPA) in postmenopausal patients with advanced breast cancer. In 36 patients randomized to MPA, the levels of A (13% vs. 19%) and C (6% vs. 8%) were slightly lower than in 36 patients on MA, but D-levels (68% vs. 59%) and E1 or E2, were similar. The correlation between baseline C and A disappeared during treatment. Treatment levels of E1 and E2 were correlated. There was no correlation between individual drug levels and any steroid, indicating a maximal suppression. After ingestion of a single dose of MA or MPA, peak levels were found after 2-3 h for MA and 3-4 h for MPA. Four hours after ingestion, the levels of A and C were similar, 40-60% of baseline values, while D levels remained unaltered. Doubling the dose of either drug did not enhance hormone suppression, indicating that the drug dosage is maximally suppressive. In conclusion, although the median serum MA levels are double those of MPA, suppression of A, C and D is usually similar, with corresponding estrogen levels, demonstrating a comparable and maximal bioavailability. Higher dosages of MA or MPA will not increase their pharmacological effects any further.

Both the efficacy and toxicity of short intensive cisplatin-based chemotherapy was established in an unselected group of patients with stage III-IV ovarian cancer. The impact of this treatment on quality of life (QOL) was assessed by the TWIST index, expressed as Time Without Symptoms of Treatment and Disease, in relation to the individual length of progression free survival (PFS). Sixty-eight patients were treated with six cycles of a combination of cyclophosphamide, Adriamycin and cisplatin (CAP-5), every 4 weeks. Patients with a clinical response to treatment were evaluated by second look laparotomy (SLL), which could be performed in 52 patients. There were 20 pathological CR, seven microscopic disease, 17 PR and eight SD in these 52 patients. Median follow up at evaluation was 22 months. The median progression free survival (PFS) was 18 months and the median overall survival 22 months. The median duration of TWIST was 10 months, indicating that about 8 months were lost to symptoms due to treatment or hospital admissions for chemotherapy or laparotomy. Of 45 patients receiving six cycles, only eight patients had no symptoms of peripheral neuropathy, and four patients were free of nephropathy at the end of treatment. The overall survival for this limited duration of treatment is similar to that after more protracted treatment. Despite its limited duration, however, about 28% of the cumulative period of progression free survival is consumed by the treatment and its side-effects. Correction of PFS by TWIST may be a suitable instrument to compare the impact of different cytotoxic schedules on quality of life.

The efficacy and side-effects of megestrol acetate and medroxyprogesterone acetate in postmenopausal patients with advanced breast cancer were compared in a prospectively randomized study. The dosage of MA was 2 X 80 mg p.o. or MPA 2 X 500 mg p.o. daily, given as a secondary hormonal treatment, mostly after previous treatment with tamoxifen. Ninety-eight patients entered the study and 92 were evaluable for effect, 48 patients on MA and 44 on MPA. Age, main tumor site and prior treatment were not different, but there was a preponderance of ER-negative tumors in the MA group. Responses appeared to be more frequent in the MPA-treated group (25% vs. 43%), predominantly in bone lesions, 12% for MA and 45% for MPA. Median progression-free survival was comparable, 15 vs. 10 months, and overall survival was not different (20 vs. 16 months). Toxicity was frequent, occurring in 83% vs. 74% of patients: increased appetite, nausea and dizziness in more than 20%, and a preponderance of pyrosis and breathlessness on MA and hot flashes, sweating and tremors on MPA. Cushingoid symptoms were present in about a quarter of the patients treated for more than 3 months. The occurrence of thrombo-embolic episodes and cardiovascular events was evenly distributed. Patients on MPA had more often increase in body weight, systolic blood pressure and serum creatinine than those treated with MA. It is concluded that MPA may be more effective for treatment of bone metastases, at the expense of more progestational side-effects. The occurrence of Cushingoid effects is frequent but similar in both arms, while the incidence of cardiovascular or thrombo-embolic events cannot be related to the use of either compound.

Twenty evaluable patients with minimal residual ovarian cancer at second look laparotomy were treated with human recombinant interferon alpha-2b (IFN) intraperitoneally. The dose administered was 50 x 10(6) units once weekly for 8 weeks. Seventeen patients were evaluated by a relaparotomy: five had a pathological complete remission, four a partial response, six patients disease stabilization and two patients had progression. Three patients, two stable and one with clinical progression, had no laparotomy. Nine of the 11 patients with residual tumor smaller than 5 mm had a response, while no response was found in six patients with residuals over 5 mm. The median duration of CR is 11+ months (6-13+ months) after evaluation. For toxicity, 156 treatment cycles could be studied. Fever was seen in 80% of all cycles within 24 h following administration of IFN, in 58 cycles (37%) over 38 degrees C and in 65 cycles (43%) over 39 degrees C. Abdominal pain was slight in 32% and moderate in 3% of all cycles. The peripheral blood leukocyte counts dropped after 52% of all cycles, in 27% below 4.0, in 22% below 3.0, and in one patient below 2.0 x 10(9)/l. IFN dosage was not reduced for leukopenia, but in one patient reduction was necessary for thrombopenia, resulting from insufficient marrow reserve after a previous autologous bone marrow transfusion. Pharmacokinetic studies showed i.p. IFN levels 50-100 times the blood levels. Blood levels were still elevated 2 days after i.p. infusion, but normalized within 1 week on repeated administration. At the second instillation, lower peak serum levels were reached. In conclusion, high doses of i.p. IFN appear to be active in patients with minimal residual disease, with ongoing response in CR patients. Apart from general malaise on the day of treatment, toxicity was acceptable. IFN may be active in patients with minimal residual ovarian cancer through local as well as systemic effects.

21 patients with advanced colorectal carcinoma were entered into a phase II study to evaluate efficacy and toxicity of methotrexate (MTX), 1500 mg/m2 rapid infusion on day 1, combined with continuous infusion of 5-fluorouracil (5-FU), 600 mg/m2 per 24 h on days 1-4. 12 patients who had progressive disease during this regimen subsequently received high-dose leucovorin, 200 mg/m2 bolus injection on days 1-4, combined with 4 days' continuous infusion of 5-FU. In the MTX/5-FU group 1 pathologically proven complete remission and 3 partial remissions were seen (response rate 20%). The median progression-free interval was 30 weeks. In 12 patients with progressive disease leucovorin/5-FU stabilized disease in 2 (17%). Toxicity in both regimens was tolerable, gastro-intestinal side-effects being most frequent. There were no treatment-related deaths. Median survival time was 10 months. Serum levels of carcinoembryonic antigen before treatment or doubling-time during progression did not correlate with survival.

To establish whether alpha-fetoprotein (AFP) produced in the early post-treatment phase of a patient with a germ cell tumour of the testis or the ovary originates from the tumour or is due to an underlying disturbance in liver function, the binding of AFP to concanavalin A (Con A) was investigated as a discriminative variable. A two-step assay is described that can distinguish the type of AFP produced at levels as low as 10 ng/ml. A Con A-binding ratio of 12-43% was found in the patients with disseminated germ cell tumours and in patients with AFP-positive gastrointestinal carcinomas. AFP from the liver gives ratios below 10%.