Dt Sleijfer

Randomized trial of Bleomycin, Etoposide, and Cisplatin compared with Bleomycin, Etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer : a multiinstitutional medical research council/European organization for research and treatment of cancer trial

PURPOSEThis prospective randomized multicenter trial was designed to evaluate the efficacy of carboplatin plus etoposide and bleomycin (CEB) versus cisplatin plus etoposide and bleomycin (BEP) in first-line chemotherapy of patients with good-risk nonseminomatous germ cell tumors.PATIENTS AND METHODSBetween September 1989 and May 1993, a total of 598 patients with good-risk nonseminomatous germ cell tumors were randomized to receive four cycles of either BEP or CEB. In each cycle, the etoposide dose was 120 mg/m2 on days 1, 2, and 3, and the bleomycin dose was 30 U on day 2. BEP patients received cisplatin at 20 mg/m2/d on days 1 to 5 or 50 mg/m2 on days 1 and 2. For CEB patients, the carboplatin dose was calculated from the glomerular filtration rate to achieve a serum concentration x time of 5 mg/mL x minutes. Chemotherapy was recycled at 21-day intervals to a total of four cycles.RESULTSOf patients assessable for response, 253 of 268 (94.4%) of those allocated to receive BEP achieved a complete response...

Prediction of residual retroperitoneal mass histology after chemotherapy for metastatic nonseminomatous germ cell tumor: multivariate analysis of individual patient data from six study groups.

PURPOSE To develop a statistical model that predicts the histology (necrosis, mature teratoma, or cancer) after chemotherapy for metastatic nonseminomatous germ cell tumor (NSGCT). PATIENTS AND METHODS An international data set was collected comprising individual patient data from six study groups. Logistic regression analysis was used to estimate the probability of necrosis and the ratio of cancer and mature teratoma. RESULTS Of 556 patients, 250 (45%) had necrosis at resection, 236 (42%) had mature teratoma, and 70 (13%) had cancer. Predictors of necrosis were the absence of teratoma elements in the primary tumor, prechemotherapy normal alfa-fetoprotein (AFP), normal human chorionic gonadotropin (HCG), and elevated lactate dehydrogenase (LDH) levels, a small prechemotherapy or postchemotherapy mass, and a large shrinkage of the mass during chemotherapy. Multivariate combination of predictors yielded reliable models (goodness-of-fit tests, P > .20), which discriminated necrosis well from other histologies (area under the receiver operating characteristic (ROC) curve, .84), but which discriminated cancer only reasonably from mature teratoma (area, .66). Internal and external validation confirmed these findings. CONCLUSION The validated models estimate with high accuracy the histology at resection, especially necrosis, based on well-known and readily available predictors. The predicted probabilities may help to choose between immediate resection of a residual mass or follow-up, taking into account the expected benefits and risks of resection, feasibility of frequent follow-up, the financial costs, and the patients individual preferences.

Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group.

PURPOSE This prospective randomized trial was designed to compare the efficacy of etoposide plus cisplatin (EP) versus bleomycin, etoposide, and cisplatin (BEP) chemotherapy in patients with good-prognosis metastatic nonseminomatous testicular cancer. PATIENTS AND METHODS Four hundred nineteen patients with good-prognosis nonseminomatous testicular cancer were randomized to receive four cycles of cisplatin 20 mg/m2 on days 1 to 5 plus etoposide 120 mg/m2 on days 1, 3, and 5 with or without bleomycin 30 mg weekly. RESULTS Of 395 eligible patients, 169 of 195 patients allocated to EP (87%) and 189 of 200 patients allocated to BEP (95%) achieved a complete response with chemotherapy alone or after postchemotherapy surgery. These results are significantly different (P = .0075). After a median follow-up duration of 7.3 years, eight patients (4%) on each treatment arm relapsed. In view of the low number of unfavorable treatment outcomes (11%), no significant differences were detected in time to progression (P = .136) and survival (P = .262). Both the acute and late pulmonary toxicity and neurotoxicity were significantly greater in patients who received BEP, whereas Raynauds phenomenon occurred exclusively in patients who received BEP (P < .001). Two patients treated with BEP died of bleomycin pulmonary toxicity. CONCLUSION BEP is the most effective combination regimen in the treatment of disseminated nonseminomatous germ cell cancer. In this particular BEP regimen with etoposide at a dose of 360 mg/m2 per cycle, even in good-prognosis patients, bleomycin cannot be deleted without compromising treatment efficacy, but its use is associated with more toxicity (particularly pulmonary) and efforts to reduce this merit further exploration.

Phase II study of subcutaneous interleukin-2 in unselected patients with advanced renal cell cancer on an outpatient basis.

PURPOSE A single-institution phase II study was undertaken to evaluate the efficacy and toxicity of interleukin-2 (IL-2) administered by subcutaneous injection. PATIENTS AND METHODS Twenty-seven unselected patients (15 male) with a mean age of 60 years (range, 42 to 76 years) who had advanced renal cell cancer were treated as outpatients. IL-2 was given once a day, 5 days per week for 6 weeks. During the first 5-day cycle, 18 x 10(6) IU was given once daily; in the following cycles, the doses in the first 2 days were reduced to 9 x 10(6) IU. After a 3-week rest period, treatment was repeated in patients who had a response or stable disease (SD). To prevent pyretic reactions, patients also received acetaminophen (250 to 500 mg given orally every 4 to 6 hours). RESULTS After 6 weeks, 26 patients were assessable for response. Two patients (8%) had a complete remission (CR), four (15%) had a partial remission (PR), and 13 (50%) had SD. A second cycle of 6 weeks was given to 19 patients; one patient with a PR and six with SD showed progression. Duration of the CR was 17+ and 19+ months, and length of the PR was 2, 8, 11, and 11+ months. The median survival of the patients who were nonresponders and responders was 10 and 20+ months, respectively, and for all patients was 13 months. One patient died as a result of myocardial infarction and brain stem ischemia. Systemic side effects in the other patients were tolerated and accepted, and included transient inflammation and local induration at the injection sites, fever and chills, and nausea. CONCLUSION Subcutaneous IL-2 is clinically active, has an acceptable toxicity, and can be given to patients with concomitant disease.

Detection of recurrence in patients with clinical stage I nonseminomatous testicular germ cell tumors and consequences for further follow-up: a single-center 10-year experience

PURPOSE A wait-and-see policy for patients with stage I nonseminomatous testicular germ cell tumors (NSTGCT) was evaluated in a prospective study. The frequency and time of recurrence, detection of recurrence, and presence of unfavorable prognostic factors were investigated. PATIENTS AND METHODS During the period 1982 to 1992, 154 patients with stage I NSTGCT (median age, 29 years) underwent orchidectomy and were monitored at follow-up evaluation with physical examinations, alfafetoprotein (AFP) and beta-human choriogonadotropin (hCG) levels, chest x-rays (CXR), and computed tomographic (CT) scans of the abdomen and chest. Multivariate logistic regression analyses were performed to identify prognostic factors. RESULTS During a median follow-up period of 7 years (range, 2 to 12), recurrence was found in 42 patients (27.3%). All cases of recurrence were detected within 2 years, 90% in the first year after orchidectomy. In 29 patients (69.0%), recurrence was detected in the abdominal lymph nodes. Nine patients (21.4%) had metastases in the retroperitoneum and mediastinum and/or lungs, and four patients (9.6%) had metastases only in the mediastinum or lungs. The majority of recurrences (97.6%) were detected by tumor markers and CT scans. Recurrence was related to the presence of vascular invasion, embryonal carcinoma (E), elevated preoperative hCG level, and absence of mature teratoma (M). Only vascular invasion was an independent risk factor. After polychemotherapy treatment for recurrence, the survival rate for the total group was 98.7%. CONCLUSION The wait-and-see policy is a reliable method for follow-up monitoring of patients with stage I NSTGCT. Even in patients with unfavorable prognostic factors, it is justified to await the possible appearance of metastases. For the future, it is recommended that CXR be omitted from the schedule, and it might be feasible to discontinue follow-up evaluations after 5 years.

Four cycles of BEP vs four cycles of VIP in patients with intermediate-prognosis metastatic testicular non seminoma : a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group

We investigated the efficacy and toxicity of induction chemotherapy with cisplatin and etoposide with either bleomycin or ifosfamide in patients with intermediate-prognosis testicular non-seminoma. A total of 84 eligible patients were randomized to receive four cycles of etoposide, ifosfamide, cisplatin (VIP), or four cycles of bleomycin, etoposide, cisplatin (BEP). Intermediate prognosis was defined as any of the following: lymph node metastases 5-10 cm in diameter, lung metastases more than four in number or > 3 cm, HCG 5000-50,000 IU l(-1), AFP > 1000 IU l(-1). The complete response (CR) rates to VIP and BEP were similar, 74% and 79% respectively (P = 0.62). Including the cases in whom viable cancer was completely resected with post-chemotherapy debulking surgery, the percentages of patients who achieved a no-evidence-of-disease status were 80% on VIP and 82% on BEP (P = 0.99). In addition, there were no differences in relapse rate, disease-free and overall survival after a median follow-up of 7.7 years. The 5-year progression-free survival was 85% (95% CI 74-96%) in the VIP arm and 83% (95% CI 71-96%) in the BEP arm, hazard ratio (VIP/BEP) 0.83 (95% CI 0.30-2.28). The VIP regimen was more toxic with regard to bone marrow function; the frequency of leucocytes below 2000 microl(-1) throughout four cycles was 89% on VIP and 37% on BEP (P < 0.001). Our study does not indicate that ifosfamide is superior to bleomycin in combination with cisplatin and etoposide. The sample size in this study is small as the study was prematurely discontinued when data became available from a competing study that showed no improved effectiveness of VIP compared with BEP. Taken together with these data, bleomycin should not be replaced by conventional-dose ifosfamide.

Gonadal function after surgery and chemotherapy in men with stage II and III nonseminomatous testicular tumors.

The gonadal functions were studied in 54 patients with disseminated nonseminomatous testicular tumors who had been subjected to combination chemotherapy (cisplatin, vinblastine, and bleomycin [PVB]) and surgery (hemiorchiectomy, retroperitoneal lymph node dissection or removal of retroperitoneal residual tumor after chemotherapy) and in 17 patients with a stage I tumor subjected to hemiorchiectomy exclusively. In the patients treated with chemotherapy, the plasma testosterone levels remained at the lower limit of normal and the luteinizing hormone (LH) levels remained elevated for 2 years after completion of treatment. The follicle-stimulating hormone (FSH) levels also remained significantly elevated, but showed a tendency to decrease after 2 years. Semen analysis was performed in 25 patients; of the other patients, 18 had no antegrade ejaculation, eight had undergone a vasectomy and three patients did not cooperate. Before treatment, 72% of the patients showed azoo- or oligozoospermia; 2 years after discontinuation of the chemotherapy, 48% had azoo- or oligozoospermia while 28% had more than 60 X 10(6) spermatozoa/mL. However, interestingly the proportion of patients with azoospermia had increased from 4% to 28%. In the course of this study, eight pregnancies occurred; one ended in an early spontaneous abortion; the other seven pregnancies ran an uncomplicated course. Seven healthy children were born. In 17 patients with a stage I tumor treated by hemiorchiectomy only, the testosterone, LH and FSH levels were also observed for 2 years; until 2 years after treatment, the testosterone levels remained lower and the FSH levels remained higher than normal. Insufficiency of the Leydigs cells in the unaffected gonad appeared to be responsible for the altered hormone concentrations in the blood.

Long-term Follow-up of Cardiovascular Risk Factors in Patients Given Chemotherapy for Disseminated Nonseminomatous Testicular Cancer

OBJECTIVE To assess cardiovascular risk factors over time in patients who received chemotherapy for disseminated testicular cancer and were apparently cured. DESIGN Cohort study. SETTING Referral center. PATIENTS Fifty-seven consecutive patients (median age, 28 years; range, 16 to 43 years) who received cisplatin-containing chemotherapy between 1978 and 1985. MEASUREMENTS Serum cholesterol and high-density lipoprotein (HDL) levels, body mass index (BMI), blood pressure, kidney function, and hormonal status were monitored during follow-up after chemotherapy (median follow-up, 88 months; range, 56 to 143 months). The BMI and cholesterol values obtained 4 to 6 years after chemotherapy were compared with values from a sample of healthy, age-matched Dutch men; the cholesterol level was also compared with that of 31 patients treated with orchidectomy for stage I disease. RESULTS The mean cholesterol level in patients at the start of chemotherapy was 3.96 +/- 0.98 mmol/L [153 +/- 38 mg/dL], increasing 4 to 6 years later to 6.12 +/- 1.20 mmol/L [237 +/- 46 mg/dL] (P less than 0.001); 49 of 57 patients had an elevated low-density lipoprotein (LDL) cholesterol level (greater than 3.4 mmol/L [130 mg/dL]), with a mean level of 4.47 +/- 1.05 mmol/L [173 +/- 41 mg/dL]. Compared with a sample of healthy Dutch men, the chemotherapy group had an elevated cholesterol level (P less than 0.05). At 4 to 6 years, the mean HDL cholesterol level was 0.76 +/- 0.18 mmol/L [29 +/- 7 mg/dL], which was low compared with that of the healthy Dutch men (P less than 0.05). The mean BMI for all patients was 2.8% higher than expected 4 to 6 years after chemotherapy (P less than 0.01) but was not higher than expected 7 to 10 years after chemotherapy. CONCLUSIONS In addition to other known late side effects of chemotherapy in patients with testicular cancer, hypercholesterolemia and overweight might represent risk factors for cardiovascular disease in such patients, especially in those who are younger.

Four cycles of BEP versus an alternating regime of PVB and BEP in patients with poor-prognosis metastatic testicular non-seminoma; a randomised study of the EORTC Genitourinary Tract Cancer Cooperative Group.

We have investigated whether an alternating induction chemotherapy regimen of PVB/BEP is superior to BEP in patients with poor-prognosis testicular non-seminoma. A total of 234 eligible patients were randomised to receive an alternating schedule of PVB/BEP for a total of four cycles or four cycles of BEP. Poor prognosis was defined as any of the following: lymph node metastases larger than 5 cm, lung metastases more than four in number or larger than 2 cm, haematogenic spread outside the lungs, such as in liver and bone, human chorionic gonadotrophin > 10,000 IU l-1 or alphafetoprotein > 1000 IU l-1. The complete response (CR) rates to PVB/BEP and BEP were similar, 76% and 72% respectively (P = 0.58). In addition, there was no significant difference in relapse rate, disease-free and overall survival at an average follow-up of 6 years. The 5-year progression-free and survival rates in both treatment groups were approximately 80%. The PVB/BEP regime was more toxic with regard to bone marrow function; the frequencies of leucocytes below 1000 microliters-1, leucocytopenic fever and platelets below 25,000 microliters-1, throughout four cycles were 28% vs 5% (P < 0.001), 16% vs 5% (P = 0.006), and 10% vs 1% (P = 0.001) respectively. Neuropathy also occurred more often in the PVB/BEP arm: 47% vs 25% (P = 0.001). This study shows that an alternating regimen of PVB/BEP is not superior to BEP and that it is more myelo- and neurotoxic.

Malignant struma ovarii treated by ovariectomy, thyroidectomy, and 131I administration

A 36‐year‐old woman presented with an intraperitoneally disseminated malignant struma ovarii, diagnosed by histopathology and 131I scintigraphy. The serum thyroglobulin level was elevated, and immunoperoxidase staining for thyroglobulin was positive for disease both in the tumor cells lining the follicles and in the colloid. The patient was treated successfully by a bilateral ovariectomy followed by a total thyroidectomy and administration of radioactive iodine. The clinical behavior and the presence of thyroglobulin in both serum and tumor tissue demonstrate the similarity between neoplastic thyroid tissue in the ovary and in the thyroid gland.