Treatment of invasive grade 3 transitional cell bladder cancer. A retrospective study of 10 years' experience with external irradiation, and preoperative irradiation and cystectomy.

Three hundred and seventy-four patients with invasive grade 3 bladder cancer treated with either external irradiation or preoperative irradiation and cystectomy were re-evaluated. Cancer-free survival was markedly better for patients who underwent preoperative irradiation and operation than irradiation only, even if a complete clinical response had occurred initially.

Phenotypes of placental-type alkaline phosphatase in seminoma sera as defined by monoclonal antibodies.

PLAP-like enzymes could be detected in serum of patients with primary testicular tumors, in particular seminomas. The use of a panel of monoclonal antibodies (MAbs) permitted typing into 6 different testicular serum phenotypes, of which one appeared similar to a placental type (II) and 2 have not been previously described. Most tumor sera belonged to type I, as described for seminoma tissues. With a more advanced tumor the mean serum PLAP-like levels increased. After operation, after radiotherapy or with no evidence of disease lower or non-detectable enzyme levels were found. In typing the tissue PLAP-like antigen in serum of the same patient or sera from recurrences of a seminoma in the same patient, the same phenotypes of PLAP-like antigen were usually but not always found. None of the 6 phenotypes appeared to confer a poorer prognosis. We conclude that the expression of PLAP-like antigen is eutopic and is enhanced by testicular malignancy, especially in seminoma cells.

Bestatin treatment enhances the recovery of radiation induced impairments of the immunological reactivity of the blood lymphocyte population in bladder cancer patients.

Bestatin, an immunostimulating substance of microbial origin, was examined for its capacity to augment immune responses of blood lymphocytes in bladder cancer patients having received a full course of local irradiation (64 Gy). Following irradiation the patients became lymphopenic and the lymphocytes exhibited impaired mitogenic responses to phytohemagglutinin (PHA) and purified protein derivative of tuberculin (PPD) and reduced poke weed mitogen induced secretion of immunoglobulins in vitro. Patients who were randomized to receive daily oral Bestatin treatment exhibited enhanced recoveries of PHA- and PPD-responses and enhanced recovery of the IgM secreting capacity compared to irradiated patients who did not receive Bestatin. Repopulation of the blood lymphocyte population, however, was not enhanced by Bestatin treatment. It is concluded that Bestatin treatment may enhance the recovery of radiation induced functional defects of the immune system in cancer patients.

Irradiation therapy with multiple small fractions per day in urinary bladder cancer.

In a clinical trial 168 patients with carcinoma of the bladder, T2-T4, were randomized to one of two treatments; 1 Gy 3 times a day to a total of 84 Gy or 2 Gy once a day to a total of 64 Gy. Local eradication of the tumour in the bladder cystoscopically and cytologically at 6 months after completion of treatment and patient survival were analyzed. The results favoured significantly the patients treated with 84 Gy. All patients were followed 5-9 years. The survival was significantly improved in patients with T3 lesions treated with 84 Gy (p less than 0.01). Complications in the bowel requiring surgical treatment were not significantly different between the two groups of patients. The results indicate a therapeutic gain by hyperfractionated radiotherapy in comparison to conventional fractionated radiotherapy.

Combined bleomycin and radiation therapy in carcinoma of the penis.

Cancer of the penis is an uncommon disease in the western part of the world but it represents a significant portion of male cancer in other countries as in Asia, Africa, and South America, where in certain areas it accounts for 20% of the cancer occurrence in male patients. The treatment has been based mainly on surgical excision with or without regional lymphadenectomy. Chemotherapy with bleomycin has had some effectiveness in advanced disease. A mode of combination therapy with bleomycin and irradiation has been evaluated in patients with carcinoma of the penis. The results compare favorably with surgical treatment with respect to cure of the disease and patient survival, and it has the advantage of preserving sexual function in most of the cases. This combined therapy is useful even in patients with relatively extensive local tumor.

Interferon therapy in disseminated renal cell carcinoma.

Twenty patients with pulmonary metastases of renal cell carcinomas have been treated in a randomized study with either leucocyte interferon in daily doses of 3 x 10(6) I.U.i.m or irradiation of both lungs in a calculated mean central dose of 10 Gy in 4 weeks in combination with bleomycin and vincristine. Most patients had a short time to progression of their disease. Three patients in the interferon group had complete response (CR) and partial response (PR) and one patient in the other group had PR. The numbers of patients in both arms of the study are too small to allow any conclusions whether beneficial effects are more frequent in one group than in the other, but there is a more favourable tendency in the interferon group.

Pharmacokinetic study of i.v. infusions of adriamycin.

The plasma pharmacokinetics of adriamycin has been studied in 21 cancer patients (31-85 years old) without liver tumours after short (3.00 min) and prolonged (45 min-16 h) i.v. infusions. The area under the plasma concentration-time curve and the maximum plasma concentration compensated for dose variation showed a more than 3-fold individual variation. The pharmacokinetics of adriamycin was linear. There was no pharmacokinetic rational for variation of the dose with the age of the patients. There was good agreement between the measured plasma concentration-time curves for prolonged infusions and curves predicted from pharmacokinetic data from short term infusions.

Intravesical instillation of adriamycin: influence on bladder capacity.

The bladder capacities of 75 patients with superficial bladder tumors were measured prior to and during monthly intravesical instillation therapy with adriamycin. When taken off therapy, a decrease in bladder capacity of more than 20% was observed in 18 of the patients. In 14 of the treated patients an increase in bladder capacity of more than 20% was observed. In patients with reduced bladder capacity when taken off therapy, there were no correlations between the degree of decreased bladder capacity and the number of instillations or the total instilled amount of adriamycin, indicating that the observed decrease in bladder capacity was caused by the underlying disease and not by the treatment per se.

Hypocholesterolemia in cancer patients may be caused by elevated LDL receptor activities in malignant cells.

Several epidemiological studies indicate an inverse relation between plasma cholesterol and the occurrence of cancer. Since we in previous studies have found that certain malignant cell types have an elevated LDL receptor activity, the aim of the present study was to further explore the possibility that an elevated LDL consumption by tumor cells causes hypocholesterolemia. The plasma cholesterol concentrations in patients with acute leukemia were inversely correlated with the rate of receptor-mediated degradation of 125I-LDL by the leukemic cells. During chemotherapy, the total plasma and the LDL cholesterol levels increased concomitantly with the reduction in the leukemic cell count in a patient whose leukemic cells exhibited a high rate at receptor-mediated degradation of 125I-LDL. In certain patients with inoperable urinary bladder carcinoma, the plasma cholesterol concentration fell as the disease progressed. Studies in breast cancer patients indicate that the number of LDL receptors in the tumor tissue may have prognostic significance. The results are in agreement with the hypothesis that an elevated LDL receptor activity in malignant cells may lead to hypocholesterolemia.

Irradiation, chemotherapy and surgery in esophageal cancer: a randomized clinical study. The first Scandinavian trial in esophageal cancer.

In a randomized trial, irradiation alone (35 Gy) or irradiation (30 Gy) and bleomycin was given as preoperative treatment of esophageal cancer. In inoperable patients, a split course of irradiation alone (63 Gy) or irradiation (55 Gy) and bleomycin was given. Bleomycin doses were 5 mg i.m. 1/2-1 h before each irradiation dose. No benefit was obtained by addition of bleomycin to irradiation concerning survival or palliation of dysphagia. No benefit of bleomycin was seen either in any subgroup of patients according to different primary tumour classifications, histopathological gradings or localizations of tumour. In patients with advanced/metastatic disease, bleomycin and adriamycin treatment gave a significantly longer survival than bleomycin alone. It was shown that the presence of T1 tumours was a significant prognostic factor for long-term survival and that performing a radical operation was a significant advantage for a longer survival. Female patients treated with irradiation with or without bleomycin survived significantly longer than males, but in operable patients there was no significant difference between the two sexes with regard to survival.

Chemotherapy in advanced urinary bladder cancer.

In our investigation of different chemotherapy protocols, the best results in recent years were obtained with a combination of cisplatinum and doxorubicin in patients with recurrent urinary bladder cancer. This applied both to the local bladder tumor and the metastases. With respect to the cases of advanced localized bladder cancer, refined surgery or more developed equipment in radiotherapy, even developing new particles or rays, presumably will give only marginal effects on eradication of the tumor. A new approach may be to give a combined therapy of CDDP and doxorubicin before surgery and/or radiotherapy; a pilot study is going on in Stockholm. Experience so far has shown that CDDP together with radiotherapy or after preoperative irradiation followed by cystectomy is not tolerable to the patients. Between 40 and 50 per cent of them failed to fulfill the treatment.

Immunological and haematological monitoring in bladder cancer patients receiving adjuvant bestatin treatment following radiation therapy. A prospective randomized trial.

In a prospective randomized trial the clinical value of Bestatin, a low molecular weight immunomodulator, is being examined in patients having completed a full course of local radiation therapy for bladder cancer. At termination of irradiation (64 Gy in eight weeks) the patients are divided into two treatment arms: (i) 10 mg of Bestatin orally three times daily without breaks for at least one year and (ii) no further adjuvant treatment. Routine haematological monitoring of 68 patients for a period of up to two years did not reveal any differences between the two groups. Studies on the blood lymphocyte population, however, showed a significantly elevated frequency of cells forming rosettes with sheep erythrocytes after one month of Bestatin treatment. Upon continuation of treatment, however, this value declined and reached the level of the control patients at three months. The frequencies of lymphocytes with Fc-receptors for IgG or complement were unaffected by Bestatin. Spontaneous cytotoxicity against Chang cells appeared to be increased during the first three months of Bestatin treatment in those patients who survived for more than 18 months. No increase was observed in patients who died earlier. Although the above data seem to indicate that Bestatin should be administered at higher doses and intermittently instead of continuously, our preliminary results on disease-free survival in a limited patient material seem to be in favour of the Bestatin treated patients.

The value of preoperative classification according to the TNM system. A critical examination of Category T2 in 96 patients with grade 3 transitional cell bladder carcinoma subjected to preparative irradiation and cystectomy.

A critical reevaluation of the preoperative classification in 96 patients with transitional cell bladder carcinomas of grade 3 (WHO) and clinical category T2 has been performed. As a result of incomplete biopsies and clinical data, it was possible to reclassify only 49 tumors (51%). 43 of these seemed to be of a lower stage than originally proposed. In addition downstaging after preoperative irradiation occurred in 77 patients (80%). In view of the uncertainties in the present series, a return to a simplified preoperative classification for clinical purposes is proposed--e.g. tumors with mucosal growth, tumors with muscle infiltration, tumors extending outside the bladder.

Possibilities for an extended classification of bladder cancer.

Patients with bladder cancer were evaluated for T-class, histo-pathological grade and U-CEA (urinary carcinoembryonic antigen) before treatment and the cytological picture 4 months after treatment. Previous work has shown that these variables are not significantly intercorrelated. Scores were computed, consisting of the sums of these (dichotomized) variables. In a statistical analysis with the life-table technique, the scored variables have been log-rank tested for a prognostic trend. In 155 patients, p for symptom-free survival between subgroups with low and high scores was 0.0019 and for relative survival 0.0005. This implies that a combination of variables may have predictive value in bladder cancer.

Distribution of lymphocyte subsets following radiation therapy directed to different body regions.

Local radiation therapy may severely deplete the recirculating pool of lymphocytes as manifested by a reduction of blood lymphocyte counts. There is considerable controversy, however, concerning the changes of the distributions of subsets of blood lymphocytes during the acute and late phases after irradiation. This report provides evidence that radiation therapy directed to different anatomic sites may change the distribution of subsets of blood lymphocytes in different ways. For instance, during the acute phase after radiation therapy for breast cancer there is a more extensive reduction of the proportion of lymphocytes with receptors for C3 than that of lymphocytes with receptors for sheep erythrocytes (characteristics of B- and T-cells respectively). Such a difference, however, was not observed in groups of patients receiving pelvic irradiation. The controversy in the literature concerning the distribution of lymphocyte subsets after irradiation may thus in part be due to the fact that the patients examined have received radiation therapy to different body regions.

[Adriamycin instillations in carcinoma in situ of the bladder]. / Adriamycin-Instillationen bei Carcinoma in situ der Harnblase.

Several authors have described the regressive effect of the instillation of adriamycin on the cell appearance of carcinoma in situ. This applies to both weekly and monthly administration. The problem lies in the interpretation of the cytologic picture after instillation. DNA analysis could possibly improve the diagnostic reliability.

A clinical evaluation of serum placental alkaline phosphatase in seminoma patients.

Serum levels of placental alkaline phosphatase (PLAP) were measured in 100 patients with seminoma. A specific double antibody radioimmunoassay was used. PLAP was elevated for 9 out of 21 patients with primary tumours, to a mean of 53 micrograms/l. Of the 12 cases with recurrent or metastatic growth, nine had raised PLAP. The sensitivity of PLAP determinations for primary and advanced disease was 55%. After successful treatment of seminoma, the PLAP level decreased. In a group of 68 patients with no evidence of disease, nine had slightly elevated serum PLAP. In many, but not all patients, serum PLAP parallelled the changes in tumour burden. In such patients and for follow-up of treatment, PLAP might be used as a new marker for seminomatous disease.

Spontaneous cytotoxicity of blood lymphocytes following local radiation therapy for carcinoma of the urinary bladder.

The spontaneous cytotoxicity of blood lymphocytes was examined before and after local radiation therapy (64 Gy) for transitional cell carcinoma of the bladder. The lymphocyte count was reduced to approximately 40 per cent at termination of treatment and remained below the pre-treatment level during a follow-up period of 18 months. The relative spontaneous cytotoxicity for 51Cr-labelled K562 cells, derived from a human myeloid leukemia, increased at completion of irradiation and remained elevated during the entire observation period. The relative cytotoxicity against Chang cells, derived from human liver, also seemed to increase but not to the same extent. The increments were probably due to an increased proportion of spontaneously cytotoxic cells bearing Fc-receptors for IgG which were significantly elevated after treatment. It was concluded that the changes differ from those occurring after local irradiation for breast carcinoma. The proportion of lymphoid tissue in relation to the blood volume which is included in the irradiated field may determine the changes of the blood lymphocyte population.

Intravesical chemotherapy in urinary bladder cancer.

Monthly instillation therapy with Adriamycin in a standardized dose of 300 ng/ml/h together with a phosphate buffer at pH 7.4 seems to give satisfactory results in patients with primary bladder carcinoma in situ and in patients with secondary carcinoma in situ of the bladder who have previously received full courses of irradiation. The side-effects are transient and few.