Combined treatment with pemetrexed and vinflunine in patients with metastatic urothelial cell carcinoma after prior platinum-containing chemotherapy - results of an exploratory phase I study.

Vinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 280 mg/m2 on day 1 of a 21-day cycle. Three levels of pemetrexed were planned starting at 400 mg/m2. Four patients were enrolled with a mean age of 66 years and with a mean number of prior GC-cycles of 6,8. Two DLT's were observed at the lowest dose-level in cohort 1. One patient experienced grade 4 thrombocytopenia and a second demonstrated hepatobiliary toxicity grade 3 with an increase in alanine aminotransaminase. Most common grade 3 and 4 adverse events were anemia, thrombocytopenia and neutropenia. Three out of four patients received 3 cycles of pemetrexed and vinflunine, all had progressive disease. Based on these observations and due to protocol design, the study was interrupted at dose level 1 for safety reasons. The combined therapy of vinflunine (Javlor®, Pierre Fabre Pharma) and pemetrexed (Alimta®, Eli Lilly) is poorly tolerated in metastatic UCC patients. The combination cannot be recommended for further investigations in metastatic UCC.

Screening for carcinoma in situ in the contralateral testicle in patients with testicular cancer: a population-based study.

BACKGROUND: Screening programmes for contralateral carcinoma in situ (CIS) testis in patients with unilateral germ-cell cancer (GCC) have never been evaluated. We investigated the effect of screening for contralateral CIS in a large nation-wide, population-based study. PATIENTS AND METHODS: A contralateral single-site biopsy was offered to 4130 patients in whom GCC had been diagnosed in 1984-2007 (screened cohort); 462 patients in whom GCC was diagnosed in 1984-1988 comprised the unscreened cohort. Cases with CIS were offered radiotherapy. Initially CIS-negative biopsies in patients with metachronous GCC were revised according to today's standards. Risk for metachronous GCC was estimated using cumulative incidence and the Cox proportional hazards model. RESULTS: In the screened cohort, contralateral CIS was found in 181 (4.4%) patients. The cumulative incidence of metachronous GCC after 20 years was 1.9% in the screened cohort and 3.1% in the unscreened cohort (P = 0.097), hazard ratio (HR) for the unscreened cohort: 1.59 (P = 0.144). Expert revision with contemporary methodology of CIS-negative biopsy samples from patients with metachronous cancer revealed CIS in 17 out of 45 (38%) cases. Decreased risks for metachronous GCC were related to older age at diagnosis (HR 0.52 per 10 years, P < 0.001) and chemotherapy (HR 0.35, P = 0.002). Limitations include the small number of patients in the unscreened cohort and the retrospective study design. CONCLUSIONS: Our evaluation of a national population-based screening programme for contralateral CIS in patients with testicular cancer showed no significant difference in the risk for metachronous GCC between a screened and an unscreened cohort. Single-site biopsy including modern immunohistochemistry does not identify all cases of CIS.

Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy.

BACKGROUND: To compare long-term, updated overall survival (OS) of patients with advanced transitional cell carcinoma of the urothelium (TCCU) treated with vinflunine plus best supportive care (BSC) or BSC alone, after failure of platinum-based chemotherapy. PATIENTS AND METHODS: Three hundred and seventy patients were randomly assigned in a phase III trial and allocated (2:1) to vinflunine (320 or 280 mg/m(2)) plus BSC or BSC alone. The first report (Bellmunt J, Theodore C, Demkov T et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinumcontaining regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol 2009; 27(27): 4454-4461) had a median follow-up of 22.1 m and the current report has a follow-up of 45.4 m. RESULTS: Three hundred and fifty-two patients had died (censoring rate 5%). In the intention-to-treat (ITT) population, the median OS was 6.9 m and 4.6 m for vinflunine plus BSC versus BSC alone, respectively (n.s.). In multivariate Cox analysis, the addition of vinflunine was independently correlated with improved survival (HR: 0.719; 95% CI:0.570-0.906, P = 0.0052). In the eligible population, the median OS in both the arms was 6.9 and 4.3 m, respectively (HR: 0.78; 95% CI:0.61-0.96; P = 0.0227), indicating an estimated 22% reduction in the risk of death. CONCLUSIONS: The updated OS data confirm the positive treatment effect of vinflunine on survival that was previously reported. These results are consistent over time and confirm that vinflunine is a valuable option for second-line treatment in patients with advanced TCCU after failure of platinum-based regimens.

Gemcitabine and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Advanced or Metastatic Bladder Cancer: Results of a Large, Randomized, Multinational, Multicenter, Phase III Study.

PURPOSE: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were compared in patients with locally advanced or metastatic transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with stage IV TCC and no prior systemic chemotherapy were randomized to GC (gemcitabine 1,000 mg/m2 days 1, 8, and 15; cisplatin 70 mg/m2 day 2) or standard MVAC every 28 days for a maximum of six cycles. RESULTS: Four hundred five patients were randomized (GC, n = 203; MVAC, n = 202). The groups were well-balanced with respect to prognostic factors. Overall survival was similar on both arms (hazards ratio [HR], 1.04; 95% confidence interval [CI], 0.82 to 1.32; P = .75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI, 0.72 to 1.10), and response rate (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments. The toxic death rate was 1% on the GC arm and 3% on the MVAC arm. More GC than MVAC patients had grade 3/4 anemia (27% v 18%, respectively) and thrombocytopenia (57% v 21%, respectively). On both arms, the RBC transfusion rate was 13 of 100 cycles and grade 3/4 hemorrhage or hematuria was 2%; the platelet transfusion rate was four patients per 100 cycles and two patients per 100 cycles on GC and MVAC, respectively. More MVAC patients, compared with GC patients, had grade 3/4 neutropenia (82% v 71%, respectively), neutropenic fever (14% v 2%, respectively), neutropenic sepsis (12% v 1%, respectively), and grade 3/4 mucositis (22% v 1%, respectively) and alopecia (55% v 11%, respectively). Quality of life was maintained during treatment on both arms; however, more patients on GC fared better regarding weight, performance status, and fatigue. CONCLUSION: GC provides a similar survival advantage to MVAC with a better safety profile and tolerability. This better-risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC.

Hyponatremia as a prognostic and predictive factor in metastatic renal cell carcinoma.

BACKGROUND: Low serum sodium has recently been associated with poor survival in localised renal cell carcinoma (RCC). We now show the prognostic effect of serum sodium in patients with metastatic RCC (mRCC). METHODS: Cohort A comprised 120 consecutive patients with mRCC receiving subcutaneous, low-dose interleukin-2 and interferon-alpha. Hyponatremia was assessed in univariate and multivariate analyses. An independent cohort of another 120 patients with mRCC was used for validation (cohort B). RESULTS: In cohort A, estimated 5-year survival was 15% and median survival was 15.1 months. Serum sodium ranged between 126 and 144 mM. Twenty-four patients (20%) had serum sodium levels below normal range (<136 mM). In multivariate analysis, significant independent risk factors for short survival were low serum sodium (P=0.014), high neutrophils (P=0.018), lactate dehydrogenase >1.5 upper normal level (P=0.002), and number of metastatic sites (+3) (P=0.003). In cohort B, serum sodium ranged between 128 and 146 mM. Seventeen patients (14%) had sodium levels below normal range. In multivariate analysis, serum sodium was validated as an independent prognostic factor (P=0.001). A significant association between lack of response and hyponatremia was observed in both cohorts (P=0.003 and P=0.02, respectively). CONCLUSION: Low serum sodium is a new, validated, independent prognostic, and predictive factor in patients with mRCC.

Chemotherapy-induced nausea, vomiting, and fatigue--the role of individual differences related to sensory perception and autonomic reactivity.

BACKGROUND: In spite of antiemetics, postchemotherapy side effects continue to be common and may affect compliance to cancer treatment. Among the known factors associated with increased symptom severity are: younger age, treatment toxicity, expected severity, and distress, but little is still known about the role of other factors. The aim of our study was to investigate the role of individual differences related to sensory perception for posttreatment side effects. METHODS: Hundred and twenty-five women receiving adjuvant chemotherapy for breast cancer completed measures of absorption, autonomic perception, somatosensory amplification, trait anxiety, and expected severity at baseline. Pretreatment distress and posttreatment nausea, vomiting, and fatigue were assessed at the 1st, 4th, 6th and last cycles of chemotherapy. RESULTS: While univariate analyses showed several factors to be associated with side effects, only absorption and pretreatment distress remained independent predictors of nausea and fatigue when controlling for the remaining factors. Posttreatment vomiting was only predicted by expected severity of vomiting. CONCLUSION: Chemotherapy-induced side effects are related to increased autonomic nervous system activity, and absorption has been associated with increased autonomic nervous system reactivity to stress. The results suggest that individuals with high absorption may be at greater risk for developing side effects. Improved precision in identifying patients at risk of experiencing more severe side effects after cancer treatment will increase the ability to target treatments aimed at reducing these side effects.

Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial.

BACKGROUND: Adjuvant radiotherapy is effective treatment for stage I seminoma, but is associated with a risk of late non-germ-cell cancer and cardiovascular events. After good results in initial studies with one injection of carboplatin, we undertook a large randomised trial to compare the approaches of radiotherapy with chemotherapy in seminoma treatment. METHODS: Between 1996 and 2001, 1477 patients from 70 hospitals in 14 countries were randomly assigned to receive radiotherapy (para-aortic strip or dog-leg field; n=904) or one injection of carboplatin (n=573; dose based on the formula 7x[glomerular filtration rate+25] mg), at two trial centres in the UK and Belgium. The primary outcome measure was the relapse-free rate, with the trial powered to exclude absolute differences in 2-year rates of more than 3%. Analysis was by intention to treat and per protocol. This trial has been assigned the International Standard Randomised Controlled Trial Number ISRCTN27163214. FINDINGS: 885 and 560 patients received radiotherapy and carboplatin, respectively. With a median follow-up of 4 years (IQR 3.0-4.9), relapse-free survival rates for radiotherapy and carboplatin were similar (96.7% [95% CI 95.3-97.7] vs 97.7% [96.0-98.6] at 2 years; 95.9% [94.4-97.1] vs 94.8% [92.5-96.4] at 3 years, respectively; hazard ratio 1.28 [90% CI 0.85-1.93], p=0.32). At 2 years' follow-up, the absolute differences in relapse-free rates (radiotherapy-chemotherapy) were -1.0% (90% CI -2.5 to 0.5) by direct comparison of proportions, and 0.9% (-0.5 to 3.0) by a hazard-ratio-based approach. Patients given carboplatin were less lethargic and less likely to take time off work than those given radiotherapy. New, second primary testicular germ-cell tumours were reported in ten patients allocated irradiation (all after para-aortic strip field) and two allocated carboplatin (5-year event rate 1.96% [95% CI 1.0-3.8] vs 0.54% [0.1-2.1], p=0.04). One seminoma-related death occurred after radiotherapy and none after carboplatin. INTERPRETATION: This trial has shown the non-inferiority of carboplatin to radiotherapy in the treatment of stage I seminoma. Although the absence of disease-related deaths and preliminary data indicating fewer second primary testicular germ-cell tumours favour carboplatin use, these findings need to be confirmed beyond 4 years' follow-up.

Long-term survival results of a randomized trial comparing gemcitabine/cisplatin and methotrexate/vinblastine/doxorubicin/cisplatin in patients with locally advanced and metastatic bladder cancer.

PURPOSE: To compare long-term survival in patients with locally advanced and metastatic transitional cell carcinoma (TCC) of the urothelium treated with gemcitabine plus cisplatin (GC) or methotrexate/vinblastine/doxorubicin/cisplatin (MVAC). PATIENTS AND METHODS: Efficacy data from a large randomized phase III study of GC versus MVAC were updated. Time-to-event analyses were performed on the observed distributions of overall survival time and progression-free survival. RESULTS: Four hundred and five patients were randomized, 203 to the GC arm and 202 to the MVAC arm. At the time of this analysis, 347 patients have died (GC 176, MVAC 171). Overall survival was similar in both arms (HR 1.09; 95% confidence interval [CI] 0.88-1.34, P = 0.66) with a median survival of 14.0 months (95% CI 12.3-15.5 months) in the GC, and 15.2 months (95% CI 13.2-17.3 months) in the MVAC arm. The median progression-free survival was 7.7 months with GC (95% CI 6.8-8.8) and 8.3 months with MVAC (95% CI 7.3-9.7) with a HR of 1.09 (95% CI 0.89-1.34). Significant prognostic factors favoring overall survival included performance status (>70), TNM staging (M0 vs. M1), low/normal alkaline phosphatase expression, number of sites of disease <3, and the absence of visceral metastasis. By adjusting for these prognostic factors, the HR was 0.99 for overall survival and 1.01 for progression-free survival. CONCLUSIONS: Long-term overall and progression-free survival following treatment with GC or MVAC are similar. These results strengthen the role of GC as a standard of care in patients with locally advanced and metastatic transitional-cell carcinoma (TCC).

Allelic deletions of cell growth regulators during progression of bladder cancer.

Cell growth regulators include proteins of the p53 pathway encoded by the genes CDKN2A (p16, p14arf), MDM2, TP53, and CDKN1A (p21) as well as proteins encoded by genes like RB1, E2F, and MYCL. In the present study we investigated allelic deletions of all these genes in each recurrent bladder tumor from well-defined clinical material with more than 3 years of follow-up. We followed three groups (22 or 23 patients/group) of patients with: (a) recurrent noninvasive tumors (Ta); (b) primary muscle-invasive tumors (T2-T4); and (c) progressing tumors (Ta/T1 --> T2/T4). We found a significant difference in the numbers of gene loci hit by deletions muscle-invasive versus noninvasive tumors (P = 0.0000002), with the genes most often hit by deletions in muscle-invasive tumors being TP53, RB1, and MYCL. A number of novel findings were made. Losses of MYCL and RB1 alleles were more pronounced in patients having concomitant field disease because 11 of 14 informative cases showed losses compared with 3 of 8 cases without field disease. A more pronounced deletion of TP53 (P = 0.002) and RB1 (P = 0.02) was found in the progressing tumor group compared with the recurrent noninvasive group, and, finally, the combined loss of TP53 and RB1 was present only in the progressing tumor or muscle-invasive groups. Deletion of two or more loci in TP53, MYCL, RB1, and CDKN2A was found in 10 patients in the progressing tumor group and in only 1 patient in the recurrent noninvasive group (P = 0.004). The data demonstrate that a characteristic difference between recurrent noninvasive and recurrent progressing bladder tumors is loss of cell cycle-regulatory genes in the latter group.

Recombinant interleukin-2 and lymphokine-activated killer cell treatment of advanced bladder cancer: clinical results and immunological effects.

The purpose of this study was to evaluate the efficacy of treatment with recombinant interleukin-2 (rIL-2) and lymphokine-activated killer cells in patients with advanced bladder cancer and to study the induced changes in the distribution of leukocyte subsets in blood and tumor. Nine patients with metastatic transitional cell cancer of the bladder were treated with a continuous infusion of rIL-2 combined with lymphocytes stimulated in vitro with rIL-2. None of the patients responded to the therapy despite substantial changes observed in the immunological cells, both in tumor and blood. The rIL-2 infusion induced migration of leukocytes to the tumors, which was related to increased expression of the adhesion molecule VLA-1 on both peripheral blood mononuclear cells and the endothelial cells of small tumor vessels. Only T-cells, predominately expressing IL-2 receptors, and macrophages infiltrated the tumors. Natural killer cells remained few or absent in the tumors, even though the natural killer cells in peripheral blood were activated by the treatment. This study shows that the present technique of rIL-2 and lymphokine-activated killer cell therapy is able to induce substantial changes in the immune system of patients with metastatic bladder cancer. However, this treatment did not induce tumor regression, which may be due to the advanced stage of disease.

Treatment of metastatic renal cell carcinoma by continuous intravenous infusion of recombinant interleukin-2: a single-center phase II study.

PURPOSE: A single-center phase II study was performed to evaluate the efficacy of recombinant interleukin-2 (rIL-2) administered by continuous infusion to patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Thirty-one patients with RCC were entered onto the study. rIL-2 (Proleukin; Eurocetus Corp, Amsterdam, The Netherlands) was administered intravenously in a dose of 18 x 10(6) IU/m2 per 24 hours. A maximum of two induction cycles and four maintenance cycles were given. Each induction cycle consisted of two rIL-2 infusion periods of 120 hours and 108 hours duration, respectively; these were separated by a 6-day rest period. Each maintenance cycle consisted of a 120 hours rIL-2 infusion period. RESULTS: Six of 30 assessable patients (20%) responded; two (7%) with a complete response (CR) and four (13%) with a partial response (PR). The response duration for patients with CR was 209 and 715+ days, and for those with PR 161, 197, 245, and 353 days. Seven patients had stable disease (SD) with a median duration of 261 days (range, 127 to 381 days). The overall median survival was 261 days (range, 13 to 905+ days). The most frequent toxicities requiring dose reductions of rIL-2 were: hypotension in 87% of patients, dyspnea in 32%, CNS toxicity in 55%, and an increase in serum creatinine levels in 48%. Septicemia occurred in 16% of patients. Toxicities usually reversed on interruption of rIL-2 infusion. One patient (3%) died as a result of the treatment from initial CNS toxicity followed by multiorgan failure. CONCLUSIONS: The study confirmed the antitumor efficacy of rIL-2 administered by continuous infusion in patients with metastatic RCC. The response rate was similar to that obtained by high-dose bolus injections of rIL-2. Toxicity was substantial but manageable in a specialized oncology ward without routine use of an intensive care unit.

Long-term fertility and Leydig cell function in patients treated for germ cell cancer with cisplatin, vinblastine, and bleomycin versus surveillance.

Fertility and Leydig cell function were investigated in 31 patients previously treated for nonseminomatous testicular cancer. Twenty-two patients with metastatic cancer had received cisplatin-based chemotherapy, and the median follow-up was 64 months (range, 42 to 100 months). Nine patients without metastases were treated with orchiectomy alone, and follow-up in this group was a median of 61 months (range, 40 to 77 months). None of the patients have relapsed and retroperitoneal lymph node dissection was not performed in any patient. Both the concentration of spermatozoa and the volume of the remaining testis are significantly reduced in patients who had previously received chemotherapy when compared with patients treated with orchiectomy alone (P less than .05). There were no significant differences between groups when comparing morphology, motility, and penetration of the spermatozoa. Subclinical Leydig cell dysfunction with normal testosterone and elevated luteinizing hormone (LH) was observed in one patient (11%) treated with orchiectomy alone, while 59% of the patients who had received chemotherapy had elevated LH (P less than .05). We conclude that cisplatin-based chemotherapy leads to a persistent impairment of fertility and Leydig cell function in the majority of patients with testicular cancer.

Surveillance alone versus radiotherapy after orchiectomy for clinical stage I nonseminomatous testicular cancer. Danish Testicular Cancer Study Group.

From December 1980 to January 1984, all patients with stage I nonseminomatous testicular cancer in Denmark entered a randomized trial comparing surveillance only with radiotherapy after orchiectomy. One hundred fifty patients were assessable for the final analysis. Relapse occurred in 23 patients in the surveillance group and in 11 patients in the radiotherapy group. Radiotherapy completely prevented retroperitoneal relapse; 14 retroperitoneal relapses occurred in the surveillance-only group. All relapsing patients in the surveillance-only group are without evidence of disease with a median observation time after chemotherapy of 67 months. Two of the patients with relapse in the radiotherapy group died with disease; the others are alive without evidence of disease, with a median observation time after relapse treatment of 72 months. In the surveillance group, four relapses occurred later than 2 years after orchiectomy; only one such late relapse occurred in the radiotherapy group. Four of the retroperitoneal relapses occurred without concomitant increase in the serum marker levels (alpha-fetoprotein [AFP] and human chorionic gonadotropin [HCG]). It is concluded that surveillance only should replace radiotherapy after orchiectomy as standard treatment for clinical stage I nonseminomatous testicular cancer. Improved methods for control of retroperitoneal relapses, especially of embryonal carcinomas, are needed.

Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study.

PURPOSE: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were compared in patients with locally advanced or metastatic transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with stage IV TCC and no prior systemic chemotherapy were randomized to GC (gemcitabine 1,000 mg/m2 days 1, 8 and 15; cisplatin 70 mg/m2 day 2) or standard MVAC every 28 days for a maximum of six cycles. RESULTS: Four hundred five patients were randomized (GC, n = 203; MVAC, n = 202). The groups were well-balanced with respect to prognostic factors. Overall survival was similar on both arms (hazards ratio [HR], 1.04; 95% confidence interval [CI], 0.82 to 1.32; P = .75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI 0.72 to 1.10), and response rate (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments. The toxic death rate was 1% on the GC arm and 3% on the MVAC arm. More GC than MVAC patients had grade 3/4 anemia (27% v 18%, respectively), and thrombocytopenia (57% v 21%, respectively). On both arms, the RBC transfusion rate was 13 of 100 cycles and grade 3/4 hemorrhage or hematuria was 2%; the platelet transfusion rate was four patients per 100 cycles and two patients per 100 cycles on GC and MVAC, respectively. More MVAC patients, compared with GC patients, had grade 3/4 neutropenia (82% v 71%, respectively), neutropenic fever (14% v 2%, respectively), neutropenic sepsis (12% v 1%, respectively), and grade 3/4 mucositis (22% v 1%, respectively) and alopecia (55% v 11%, respectively). Quality of life was maintained during treatment on both arms; however, more patients on GC fared better regarding weight, performance status, and fatigue. CONCLUSION: GC provides a similar survival advantage to MVAC with a better safety profile and tolerability. This better-risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC.

Localized irradiation of testes with carcinoma in situ: effects on Leydig cell function and eradication of malignant germ cells in 20 patients.

Twenty men (median age, 31 yr) previously treated for unilateral testicular cancer received localized irradiation in a dose of 20 Gray in 10 fractions for carcinoma in situ of the remaining testis. Follow-up testicular biopsies performed 3 (n = 19) and 24 (n = 14) months after the treatment showed in all cases a Sertoli cell-only pattern. Hormonal evaluation was performed before as well as 3, 12, 24, and 36 months after radiation treatment. Endocrine parameters were followed for a median of 30 months (3-36 months). Baseline serum testosterone values decreased during the follow-up period from 13.3 +/- 6.0 to 10.8 +/- 6.4 nmol/L (mean +/- SD), although the decrease was not statistically significant (P = 0.06). Serum LH values increased during the first 3 months of follow-up from 10.4 +/- 5.4 to 15.6 +/- 7.3 IU/L (P less than 0.0001) and then remained unchanged. Significant decreases in GnRH- and hCG-stimulated testosterone levels also indicated an impairment of Leydig cell function. FSH levels increased (P less than 0.0001) during the first 3 months of follow-up from 21.8 +/- 11.1 to 33.2 +/- 13.2 IU/L. We conclude that localized irradiation of 20 Gray eradicated carcinoma in situ germ cells. Development of a second testicular cancer has until now been prevented. Leydig cell function was partially impaired by the radiation dose given.

Gemcitabine in locally advanced and/or metastatic bladder cancer.

Gemcitabine is a promising new drug in patients with locally advanced and/or metastatic transitional cell carcinoma of the urothelium. The drug has been tested as a single-agent in one phase I study and four phase II studies. Gemcitabine was administered on days 1, 8 and 15 every 28 days with a dose in the phase II studies ranging from 1000 to 1250 mg/m(2). Response rates for single-agent gemcitabine in as well previously untreated as cisplatin-based pretreated patients ranged from 23 to 29% with CR rates between 4 and 13%. Toxicities were mild to modest and generally without grade 4 toxicities. The combination of gemcitabine and cisplatin has been tested in three phase II studies. Gemcitabine was administered in a dose of 1000 mg/m(2) on days 1, 8 and 15 every 28 days whereas the cisplatin dose and schedule varied. In one study, cisplatin was given in a dose of 35 mg/m(2) on days 1, 8, and 15 together with gemcitabine; in the two other studies in a dose of 70-75 mg/m(2) on day 1 or 2 in each treatment course. The response rates ranged from 42 to 66% with CR rates of 18, 21 and 28%. Median survival was reported in two of the studies, 12.5 and 13.2 months, respectively. Toxicities were generally manageable although the weekly schedule of cisplatin resulted in a high degree of grade 3-4 neutropenia and thrombocytopenia. Thus, the schedule has been optimized by use of monthly cisplatin in a dose of 70 to 75 mg/m(2). The two-drug combination of gemcitabine and cisplatin has also been compared with MVAC in a randomized phase III trial. Gemcitabine was administered in a dose of 1000 mg/m(2) on days 1, 8 and 15 and cisplatin in a dose of 70 mg/m(2) on day 2 every 28 days. The study was initiated late in 1996 and the planned recruitment of 400 patients was reached at the end of October 1998. The results are now eagerly awaited. Preliminary results for gemcitabine tested in two- and three-drug combinations with new agents such as paclitaxel have indicated response rates of up to 79% and these combinations should be further explored.

Gemcitabine and cisplatin in locally advanced and/or metastatic bladder cancer.

Although transitional cell carcinoma of the urothelium is chemosensitive, long-term disease-free survival is low. Accordingly, interest has focused on combining classically active agents like cisplatin with promising new drugs. Gemcitabine has evoked interest not only because of its intrinsic activity against this cancer, but also because of its effect of inhibiting repair of DNA that has been damaged by drugs like cisplatin. Four phase II studies have assessed the effect of a gemcitabine-cisplatin combination on advanced or metastatic bladder cancer. All the studies employed a gemcitabine dose of 1000 mg/m(2) given on days 1, 8 and 15, whereas the cisplatin dose and schedule varied, with total doses ranging from 70 to 105 mg/m(2). Overall response rates in these studies ranged from 42 to 66%, with complete responses from 15 to 28%. Toxicities, which were primarily haematological, were generally manageable. This promising two-drug combination has been compared with the standard MVAC regimen (methotrexate, vinblastine, doxorubicin, and cisplatin) in a randomised phase III trial and the results are eagerly anticipated.

A phase II study of cisplatin plus methotrexate with folinic acid rescue in metastatic or locally recurrent transitional cell carcinoma of the urothelium.

34 patients with metastatic or recurrent transitional cell carcinoma (TCC) of the urothelium were treated with cisplatin 100 mg/m2 plus methotrexate 250 mg/m2 with folinic acid rescue every 3 weeks. A response rate of 55% was achieved with two complete and 15 partial responses in 31 evaluable patients. The overall median survival was 7 months, 9 months for responding and 4 months for non-responding patients. Toxicity was generally moderate. However, 1 patient with previous infectious problems died of neutropenic sepsis. Overall, 83% of the scheduled doses of cisplatin and 96% of the scheduled doses of methotrexate were given. In conclusion, this schedule of the combination of cisplatin and methotrexate did not improve response rate or survival compared with previous studies of this two-drug combination.

Surveillance following orchidectomy for stage I seminoma of the testis.

From 1985 to 1988, 261 unselected patients entered a nationwide Danish study of surveillance only for testicular seminoma stage I. The median follow-up time after orchidectomy was 48 months, range 6-67 months. 49 patients relapsed (19%). Sites of relapse were paraaortic lymph nodes in 41 patients, pelvic lymph nodes in 5, inguinal lymph nodes in 2 and lung metastases in 1 patient. The median time to relapse was 14 months, range 2-37 months. The 4-year relapse-free survival was 80%. 37 of the relapsing patients (76%) had radiotherapy as relapse treatment. Of these patients, 4 (11%) had a second relapse and received chemotherapy. 1 died of disseminated seminoma. Of the relapsing patients, 12 (24%) had chemotherapy as relapse treatment because of bulky (11 patients) or disseminated disease (1 patient). None of these patients have had a second relapse. However, 2 patients died of infection due to chemotherapy-induced neutropenia. Thus, there have been three seminoma-related deaths (1.1%). The testicular tumour size had an independent prognostic significance. The 4-year relapse-free survivals were 94, 82 and 64% for tumours < 3, 3 to < 6 and > or = 6 cm, respectively. Patients with tumours > or = 6 cm will now be given prophylactic radiation treatment, whereas we will continue to use surveillance only after orchidectomy for patients with tumours < 6 cm.

Recombinant interleukin-2 in metastatic renal cell carcinoma--a European multicentre phase II study.

This multinational, multicentre study represents the introduction of recombinant interleukin-2 (rIL-2) in Europe. From December 1987 to June 1989, 57 eligible patients with metastatic renal cell cancer were treated with rIL-2 administered as continuous intravenous infusion. 8 out of 51 evaluable patients responded (16%), 2 complete remission (CR) and 6 partial remission (PR). 10 patients had no change (20%). The response duration for CR was 209 and 394+ days. The median response duration for PR was 371 (range 140-506+) days. Dose-limiting grade 3-4 toxicities were hypotension in 52% of the patients, arrhythmia (4%), dyspnoea (8%), creatinine rise (4%), peripheral neurotoxicity (10%) and central neurotoxicity (10%). Toxicities most often recovered solely on interrupted therapy. 2 patients died due to catheter-related septicaemia and one patient died of rIL-2 induced renal failure. The study confirmed the antitumour efficacy of rIL-2 in renal cell cancer. Toxicities were numerous, but manageable by close observation in a normal oncology ward without routine use of an intensive care unit.