Tumour marker concentration at the start of chemotherapy is a stronger predictor of treatment failure than marker half-life: a study in patients with disseminated non-seminomatous testicular cancer.

We investigated the prognostic value of the serum half-life of human chorionic gonadotrophin (HCG) and alpha-fetoprotein (AFP) during induction chemotherapy and the relative prognostic importance of initial marker concentrations and marker half-life. Marker half-lives were calculated using two abnormal values observed between day 8 and day 22 of the first chemotherapy cycle. Moreover, analyses were carried out using day 43 as the second measurement point. Treatment failure at any time was chosen as the end point. The relative prognostic influence of marker half-lives and initial marker concentrations was tested in univariate and multivariate analyses. Half-lives were considered to be prolonged if > 3 days for HCG and > 6 days for AFP. In addition, we separated patients into those with half-lives > 6 days for HCG and those with half-lives > 10 days for AFP to examine whether these long half-lives were associated with a poor prognosis. A group of 669 patients treated with cisplatin combination chemotherapy was studied. Forty-two per cent of the patients had normal HCG and 37% had normal AFP at the start of chemotherapy. At day 22, HCG was still elevated in 138 patients and AFP in 211. At day 43, the numbers of these patients were 35 and 80 respectively. Based on the measurements obtained on day 8 and day 22, a half-life of HCG > 3 days or > 6 days and/or a half-life AFP > 6 days or > 10 days did not accurately predict treatment failure (P=0.413 and P=0.851, respectively; values obtained using tests for trend). However, initial marker concentrations of HCG and/or AFP > 1000 IU l(-1) were highly significant prognosticators for treatment failure (P=0.001 and P < 0.001 respectively), independent of half-life values. Half-lives calculated with the values obtained on day 43 did not contribute to the accuracy of the prediction of treatment failure. We conclude that half-lives of HCG and AFP during induction chemotherapy are inaccurate parameters for the prediction of treatment failure. In contrast, initial serum concentrations of HCG and AFP are highly significant in the prediction of unfavourable treatment outcome.

A feasibility study of testing new drugs for small-cell lung cancer in patients with a poor performance status.

Testing of new drugs in small-cell lung cancer is definitely necessary for the development of agents that might be effective against this tumor. However, testing such drugs in previously untreated patients with a good performance status (PS) may give rise to ethical problems. When previously treated patients are used in testing, potentially effective agents could well elude discovery. Patients who are not eligible for "standard" combination chemotherapy, e.g. untreated patients with a poor PS, may be suitable for testing of new drugs. To evaluate the potential usefulness of such patients in the testing of new agents, we evaluated an effective drug (etoposide) at a relatively nontoxic dose in a group of 14 patients with a PS of 4 (WHO). Oral etoposide resulted in a response in only 3 cases, whereas 5 subjects died of therapy-related toxicity. We conclude that previously untreated patients with a poor PS are not suitable candidates for the testing of new drugs.

Long-term follow-up of non-seminomatous testicular cancer patients with mature teratoma or carcinoma at postchemotherapy surgery. EORTC Genitourinary Tract Cancer Cooperative Group (EORTC GU Group)

From 1979 to 1983 the EORTC GU Group treated 239 patients with disseminated non-seminomatous testicular cancer with combination chemotherapy comprising cisplatin, vinblastine and bleomycin in a prospectively controlled trial. The protocol required complete resection of residual masses after induction chemotherapy, provided that serum tumour markers were normal. 102 patients were operated on. 27 patients had mature teratoma (teratoma differentiated) in the resected specimens and 23 had viable cancer. Follow-up data were available for 26 and 22 of these patients, respectively. 23 of 26 patients (88%) with mature teratoma are alive and disease free after a follow-up of 53-110 months (median 92 months). 3 patients developed progressive disease; 1 died. A peculiar case of growing mature teratoma on the forearm is described. 13 of 22 patients (59%) with residual carcinoma are alive and disease free after a follow-up of 74-112 months (median 95 months). The prognosis of patients with carcinoma is shown to be correlated with the completeness of surgery, which in turn is correlated with the initial tumour mass before chemotherapy.

[Cured of testicular cancer; does life just go on?]. / Genezen van zaadbalkanker; gaat het leven gewoon voort?

From 1976 through 1979 we have treated 91 patients with disseminated non-seminomatous testicular cancer with induction chemotherapy comprising cisplatin, vinblastine and bleomycin. After 4 induction cycles complete responders went on to receive maintenance therapy with cisplatin and vinblastine for a median of one year. Fifty-seven patients (63%) are at present alive and free of disease. Seven to ten years after the start of treatment we have investigated their physical, mental and social situation by means of a questionnaire and by collection of data from the charts. It appeared that 90% of the respondents were fully employed. However, over half of the men reported symptoms of polyneuropathy and 40% experienced sexual function disturbances. Part of these problems were due to the maintenance chemotherapy, which has been abandoned in our country since 1982.

Ten-year survival and late sequelae in testicular cancer patients treated with cisplatin, vinblastine, and bleomycin.

This 10-year follow-up study of 91 patients with disseminated testicular nonseminomatous cancer, treated with cisplatin, vinblastine, and bleomycin (PVB) induction chemotherapy and vinblastine plus bleomycin maintenance chemotherapy for a planned period of 2 years, shows a 63% cure rate. The predominant long-term sequelae are neurological and sexual dysfunction in 68% and 40% of patients, respectively. Two patients died of myocardial infarction. Sixteen percent of patients developed hypertension, 23% Raynaud's phenomenon, and 25% ototoxicity. Despite the long-term side effects, 90% of the patients who responded to a questionnaire are fully employed. This study shows that the maintenance chemotherapy has contributed to the incidence and/or degree of neurotoxicity, hypertension, and renal function disturbance.

Absence of an additional fibrotic response caused by oxygen in the lungs of rats after the intratracheal administration of bleomycin.

Bleomycin 0.4, 0.6, 1.0 or 3.5 mg/kg body weight was administered via the trachea in rats. After various time intervals some of the animals were exposed to 50% oxygen for either 4 or 24 h. The rats were then sacrificed at different times. Control rats remained untreated or received physiological saline. Lung histology was studied by light microscopy. In a number of rats the lung content of hydroxyproline was determined. Mild reactions, namely increases in pneumocytes type II and macrophages, oedema and prefibrotic alterations were observed after the instillation of bleomycin. The reactions were comparable to those observed after additional hyperoxia alone. Lung hydroxyproline concentration was not increased after bleomycin plus oxygen as compared with bleomycin alone. We conclude that no added toxicity is caused by 50% oxygen supplied for 4 or 24 h subsequent to doses of bleomycin that lead to mild pulmonary abnormalities in the absence of hyperoxia.

Pulmonary toxicity after treatment with bleomycin alone or in combination with hyperoxia. Studies in the rat.

Female Wistar rats (n = 11) received bleomycin 10 mg kg-1 i.p. three times weekly for 6 weeks. Four weeks later part of the group (n = 7) were exposed to 50% oxygen in air for 4 h; the others served as unexposed controls. A further control group (n = 5) received physiological saline i.p. and was not exposed to oxygen. One week after the hyperoxia treatment all animals were sacrificed and the lungs prepared for histological and biochemical determinations. Although the average body weight of the bleomycin-treated rats decreased significantly compared with the saline-treated controls, no significant alterations in lung histology were found in regard to the occurrence of oedema, fibrosis, and type II pneumocytes. Intra-alveolar macrophages were significantly increased. Subsequent hyperoxia did not lead to a more pronounced effect, except for macrophage accumulation. The activities of superoxide dismutase and glutathione peroxidase were not changed either after administration of bleomycin alone or after combination with hyperoxia. It is concluded that bleomycin i.p. in doses comparable to those encountered clinically, administered alone or combined with hyperoxia, does not result in pulmonary damage in female Wistar rats.

High-dose versus low-dose vinblastine in cisplatin-vinblastine-bleomycin combination chemotherapy of non-seminomatous testicular cancer: a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group.

Two hundred fourteen patients with disseminated non-seminomatous testicular cancer were randomized to receive induction chemotherapy with cisplatin, vinblastine, and bleomycin (PVB). The randomization was for vinblastine 0.4 mg/kg/cycle or 0.3 mg/kg/cycle. The complete response (CR) rates to both regimens were identical: 68% and 71%, respectively. In addition, there was no significant difference in disease-free and overall survival. There was a significant decrease in the incidence of WBC nadirs below 1,000/microL: 29% and 13%, respectively (P = .01). Of the non-hematologic toxicities, there was a significant reduction in the incidence of mucositis: 53% and 37%, respectively (P = .006). The major prognostic factor was tumor volume. This study confirms that vinblastine 0.3 mg/kg/cycle in PVB chemotherapy is as effective and less toxic than vinblastine 0.4 mg/kg/cycle.

Histology and DNA contents of a secondary malignancy arising in a mature residual lesion six years after chemotherapy for a disseminated nonseminomatous testicular tumor.

The current report describes a secondary malignancy developing in a retroperitoneal mature residual lesion 6 years after chemotherapeutic treatment of a disseminated nonseminomatous testicular tumor. The histologically malignant component was not present in the primary tumor and consisted of polygonal and fusiform cells with focal tubular formations, resembling primitive neuroectodermal tissue. Immunoperoxidase staining for alpha-fetoprotein and the beta-subunit of human chorionic gonadotropin remained negative, whereas focal positivity for S100 protein was observed. Neuron specific enolase positivity was equivocal. The DNA contents of both the mature components in the primary and the metastatic retroperitoneal tumor and in the various malignant components of the primary tumor, were in the hypotriploid range. In the malignant component of the retroperitoneal metastasis, a hypertriploid peak was observed. These findings suggest further clonal evolution in a phenotypically mature, genotypically abnormal residual metastatic tumor after chemotherapy. It is stressed that the mature appearance of the residual lesions may be deceiving and that these lesions are highly susceptible to resume malignant behavior.

Five-year survival of patients with disseminated nonseminomatous testicular cancer treated with cisplatin, vinblastine, and bleomycin.

Ninety-one patients with disseminated testicular non-seminomas were treated with 3 to 4 cycles of cisplatin, vinblastine, and bleomycin (PVB) induction chemotherapy followed by cisplatin and vinblastine maintenance therapy for 1 year. The follow-up of these patients ranges from 24 to 66 months. Forty-nine (54%) patients achieved complete remission by chemotherapy alone and 14 (15%) were rendered free of tumor by surgery after chemotherapy, for a total complete remission rate of 69%. Three complete responders relapsed within 13 months, and two died. One additional complete responder died of a noncancer-related cause. One of the surgical complete responders relapsed and died. Overall, 58 (64%) patients remain free of disease. The 5-year survival is 95% for complete responders, 32% for partial responders, and 72% overall. This combination regimen has significantly improved the survival of disseminated testicular cancer patients, equaling that of Stage II patients in older literature.

Bleomycin-induced changes in the carbon monoxide transfer factor of the lungs and its components.

To study subclinical pulmonary toxicity of bleomycin we measured the single-breath carbon monoxide transfer factor (TLCO) and its components, pulmonary capillary blood volume (Vc), diffusing capacity of the alveolar-capillary membrane (Dm), and vital capacity (VC) in a homogenous group of 18 patients with testicular nonseminomatous germ cell tumor treated with bleomycin, vinblastine, and cis-diammine-dichloroplatinum (DDP). The most prominent finding was a substantial decrease in Vc (p less than 0.001) with only minor, though significant, changes in the other parameters. No recovery of pulmonary function had taken place 4 months after the last dose of bleomycin. The importance of correcting TLCO for hemoglobin concentration is shown. We conclude that vascular damage may be an important feature of subclinical pulmonary injury caused by bleomycin given in combination with vinblastine and DDP. In the postbleomycin phase, other forms of potentially lung-toxic treatment should be instituted with care.

Effects of multiple-drug chemotherapy (cis-diammine-dichloroplatinum, bleomycin, and vinblastine) on the maturation of retroperitoneal lymph node metastases of nonseminomatous germ cell tumors of the testis. No evidence for De Novo induction of differentiation.

Investigating the mechanisms underlying maturation of metastases of nonseminomatous germ cell tumors on administration of chemotherapy, the histologic characteristics of primary testis tumors was compared to the histologic characteristics of their retroperitoneal metastases in three historical patient groups. The metastases in Group I (20 patients) were not treated; those in Groups II (nine patients) and III (24 patients) were treated, respectively, with three cycles of dactinomycin and with four cycles of cis-diammine-dichloroplatinum, vinblastine, and bleomycin, before retroperitoneal lymph node dissection. In Group III there was a significant increase of metastases consisting of differentiated teratoma only, as compared to the metastases of Group I. However, both with and without chemotherapy, the metastases contained fewer areas of differentiated teratoma than the primary lesions. Metastases containing differentiated teratoma with and without other components, with one exception in Group III, were derived from primary tumors containing mature areas as well. Components other than mature teratoma were almost completely eradicated in Group III. These findings strongly suggest that selective destruction of components other than differentiated teratoma causes the mature histologic characteristics in the metastases upon administration of chemotherapy. The results do not support the hypothesis of induction of differentiation by the chemotherapeutic agents.

Non-seminomatous germ cell tumors of the testis. Immunohistochemical localization and serum levels of human chorionic gonadotropin (HCG) and pregnancy-specific beta-1 glycoprotein (SP-1); value of SP-1 as a tumor marker.

Serum levels of HCG and SP-1 and tissue localization in the primary tumors of these markers were correlated in 41 patients with advanced-stage non-seminomatous germ cell tumors (NSGCT) of the testis. In patients' serum, as well as in the primary tumor tissue, SP-1 positivity was accompanied by a concordant HCG positivity, so that it is concluded that in our patient group SP-1 does not give important additional information with respect to marker positivity not yet provided by HCG. A good correlation was found between serum levels of HCG and SP-1 in advanced-stage disease and the cellular localization of these markers in the primary tumors. Elevated serum SP-1 levels, with concordant elevation of HCG serum levels, were found mainly in cases with a histological diagnosis of choriocarcinoma or an admixture of this component in the primary tumor. Moreover, in cases of choriocarcinoma the presence of SP-1 positive syncytiotrophoblastic cells was very much comparable with the presence of HCG-positive syncytiotrophoblastic cells, whereas in syncytial giant cells associated with embryonal carcinoma HCG-positivity clearly outnumbered SP-1-positivity. This indicates a higher specificity of SP-1 for choriocarcinoma and, therefore, serum levels of this marker may have an important prognostic impact in NSGCT patients with advanced-stage disease. Apart from positivity in syncytiotrophoblastic cells of choriocarcinoma and syncytial giant cells, HCG positivity was incidentally seen in mononuclear embryonal carcinoma cells.

Tumors of the testis in two brothers: a case report.

This paper describes two nontwin brothers with a nonseminoma tumor of a testicle: an embryonal carcinoma in one and an embryonal carcinoma with seminomatous components in the other. Testicular tumors of the same type have the same frequency in twin brothers as in nontwin brothers. For the present, there is no insight into the genetic influence in the pathogenesis of testicular tumors.