Phase II studies on docetaxel alone every third week, or weekly in combination with gemcitabine in patients with primary locally advanced, metastatic, or recurrent esophageal cancer.

BACKGROUND: The purpose of these studies was to compare efficacy and toxicity of docetaxel alone with the combination of gemcitabine and docetaxel for treatment of metastatic esophageal carcinoma. PATIENTS AND METHODS: These studies enrolled patients with histopathologically verified squamous cell carcinoma or adenocarcinoma of the esophagus or cardia. Between March 1997 and June 1999, 52 patients were enrolled in the initial Phase II study (Study 1). They were scheduled for treatment with docetaxel 100 mg/m2 every third week as a 1-h infusion. The second Phase II study between September 2000 and March 2003 included 65 patients (Study II). They were given docetaxel 30 mg/m2, administered as a 30-min i.v. infusion weekly for four times, followed by 2 weeks of rest, and gemcitabine starting with a dose of 750 mg/m2 (if well-tolerated 1,000 mg/m2) on days 1 and 15, followed by 3 weeks of rest. A new cycle began on day 36. Patients were premedicated with betamethasone 8 mg p.o. on the evening before, and 8 mg i.v. 30-60 min before the docetaxel infusion. Response was confirmed by computed tomography and assessed at 12 and 24 weeks. Toxicity was assessed according to WHO scales. RESULTS: In study I, 38 out of the 52 enrolled patients were valuable. Two patients experienced complete remission (CR) (5%), 10 patients partial remission (PR) (26%), nine patients stable disease (SD) (24%), and 17 patients showed progressive disease (PD) (45%). Toxicity mainly involved leukopenia, which in some cases required hospitalization and treatment with antibiotics. In Study II, 46 out of the 65 enrolled patients (70%) were assessable. Out of these, three patients (7%) had CR, eight patients (17%) had PR, 10 patients (22%) had SD, and 25 (54%) PD. Overall response was 24% while an additional 22% showed stable disease. Toxicity mainly consisted of leucopenia and pain. CONCLUSION: Docetaxel as a single agent is active in esophageal cancer, both in treatment naive and in previously treated patients with recurrent disease. The overall response rate was 31%, with a good-safety profile. The addition of gemcitabine is well tolerated, but adds no efficacy. Weekly administration of docetaxel may be less effective. It demonstrates moderate efficacy and the doses used provide an acceptable safety profile.

Evaluation of the UBC test in the urine of healthy individuals, patients with benign disorders and urinary bladder cancer.

Using the UBC test, the specificity, sensitivity and prognostic information were evaluated in patients with recently diagnosed transitional cell carcinoma (TCC) and in a control group consisting of apparently healthy individuals and individuals with benign disorders. Frozen urine samples from the 485 individuals in the control group and 100 newly diagnosed TCC patients were analyzed with the UBC test, specific for epitopes on cytokeratin fragments released from the urothelial cells. All the samples were analyzed and corrected for creatinine. No significant concentration difference was found between males and females (p=0.65) and there was no age dependent relation. The median concentration for the entire control group was estimated at 3.7 microg/g and the 95th percentile was calculated at 53.0 microg/g. The apparently healthy individuals in the control group had a median value of 3.4 microg/g with a 95th percentile of 24.3 microg/g. An increased frequency of elevated UBC concentrations was found in some benign disorders e.g., anemia, thyroid disorders, diabetes mellitus, hyperlipemia, urosepsis and cystitis. Patients with superficial tumors exhibited a 66% sensitivity (at 95% specificity), and the UBC concentrations did not differ statistically (p=0.16) from those patients with muscle invasive lesions with a 52% sensitivity. When the UBC concentrations were related to histopathological grade, a significant concentration difference (p<0.004) was found between low grade tumors (sensitivity 41%) and high grade tumors (sensitivity 72%). Survival analysis showed that patient with muscle invasive tumors, high-grade tumors and high UBC concentrations have a significantly reduced survival (five-year survival was estimated to 30%, 35% and 30% respectively) compared to patients with superficial tumors, low-grade tumors or low UBC concentrations (five-year survival, 60%, 85% and 75% respectively). The UBC test showed good accuracy and repeatability. Clinically the test could assist in tumor grading and the detection of recurrent disease, which in turn could assist in treatment selection for the individual patient and possibly improve prognosis.

GM-CSF in chemotherapy-induced febrile neutropenia--a double-blind randomized study.

Modern chemotherapy programmes render patients susceptible to bacterial and fungal infections, and the risk of developing febrile neutropenia after a chemotherapy course is in proportion to the severity and duration of the neutropenia thus caused. This double-blind randomized study presents details of 29 patients who developed febrile neutropenia an average of 10 days after their course of chemotherapy for different types and stages of malignancy. Fourteen received granulocyte/macrophage colony stimulating factor (GM-CSF) and 15 placebo during 7 consecutive days as subcutaneous injections. The GM-CSF group demonstrated significant increases in total white blood cell count (TWBC) and absolute neutrophil count (ANC) from the morning of the third day of the study. The study concludes that GM-CSF has an important therapeutic role in the treatment of febrile neutropenia that arises during intensive chemotherapy programmes but further studies of dosage and therapy duration are required, as is the development of methods of assessing bone marrow vitality.

Anemia associated with advanced prostatic adenocarcinoma: effects of recombinant human erythropoietin.

BACKGROUND AND METHODS: Nine patients with hormone-refractory metastatic prostatic adenocarcinoma and anemia were treated with recombinant human erythropoietin (rHuEpo) at a median dose of 150 U/kg BW 3 times a week subcutaneously. Baseline hemoglobin (Hb) ranged from 70 to 116 g/L, and the study duration was 12 weeks (median patient participation period was 8 weeks). RESULTS: Four patients demonstrated a median Hb increase of 20 g/L and were considered responders. Three patients showed a median increase of 17 g/L but required blood transfusion once, and were therefore considered as partial responders. Baseline erythropoietic status showed a significant correlation between serum Epo and Hb. Inadequate Epo production, evaluated by the observed/predicted log Epo ratio, was found in two patients. Defective bone marrow activity, demonstrated by low transferrin receptor (TfR), and hypoferremia in spite of abundant iron stores were also shown. Hemorheological investigations showed elevated plasma viscosity. CONCLUSIONS: Our results indicate that suppression of erythropoiesis can be mainly explained by the depressed marrow activity. The altered hemorheology might contribute to the anemia. This anemia could possibly be corrected with rHuEpo.

Deoxythymidine kinase in the staging of prostatic adenocarcinoma.

The role of prostate-specific antigen in the management of prostatic adenocarcinoma is still not fully ascertained. Its place in the monitoring of patients who have undergone radical treatment is without question but its role in the primary assessment of a lesion is a point of continuous discussion. This study reports the analysis of prostate-specific antigen (PSA) in 92 patients with different stages of prostatic adenocarcinoma prior to treatment; in the case of the localized lesions, this was based to a great extent on the findings at lymphadenectomy. Apart from PSA analysis, deoxythymidine kinase (dTK) analyses were also performed in an attempt to discover whether the latter could provide additional information about the tumor load in the different patient categories, viz. those with lymph node involvement (group 1), those with lymph node involvement but without distant metastases (group 2), and those with disseminated disease (group 3). The median PSA and dTK values in groups 1-3 were 6.5 micrograms/L and 2.7 U/microliter, 16 micrograms/L and 2.6 U/microL, and 90 micrograms/L and 7.8 U/microL, respectively. If the two analyses were used concomitantly, they could differentiate true localized disease from metastatic in approximately 92% of cases. The combination should prove of value in the primary assessment of a patient with a newly diagnosed prostatic adenocarcinoma.

Positron emission tomography in the diagnosis and staging of urinary bladder cancer.

PURPOSE: Evaluation of positron emission tomography (PET) using (18)fl 18F-2-fluoro-2-deoxy-D-glucose (18FDG) and L-methyl-11C-methionine in the diagnosis and staging of urinary bladder carcinoma. MATERIAL AND METHODS: Twenty-three patients with biopsy-proven urinary bladder carcinoma were examined with PET after intravenous injection of 11C-methionine; 2 were also examined with 18FDG. The results from the PET investigations were compared with CT or MR findings and TNM classification before and after treatment. RESULTS: The urinary excretion of 18FDG prevented distinction of the primary tumour from the surrounding tracer. With 11C-methionine it was possible to detect 18/23 primary tumours. A trend was seen, suggesting that the higher the uptake values of 11C-methionine in the tumour, the greater the tumour stage. CONCLUSION: It is possible to visualize urinary bladder tumours larger than 1 cm in diameter with PET using (11)C-methionine, but the value of the method in the staging of the lesions is not superior to conventional methods.

Estramustine-binding protein (EMBP) in renal cell carcinoma immunohistochemistry, immunoscintigraphy and in vitro estramustine effects.

The present report shows that the human renal cell carcinoma (RCC) cell lines, A498 and CAKI-2, express the estramustine-binding protein (EMBP). The RCC cell lines investigated were highly sensitive for estramustine, with cell arrest in atypical metaphase. In vitro experiments using a fluorimetric cytotoxicity assay (FMCA) showed a pronounced cytotoxic effect mediated by estramustine. Immunohistochemical analysis of tumour specimens from patients with RCC showed positive staining for EMBP in 12/16 cases. Immunoscintigraphy was performed in an experimental system in nude mice, heterotransplanted with the CAKI-2 cell line. A radiolabelled monoclonal anti-EMBP antibody was used. The results show a specific uptake of the antibody in the RCC tumour, expressed as a percentage of the injected dose per gram tissue, which ranged from 4.03 to 6.9. The results obtained form the basis for clinical studies on the feasibility of utilizing estramustine in the management of RCC. Immunoscintigraphy using the monoclonal anti-EMBP antibody is of potential use for in vivo characterization of the malignancy and in the selection patients suitable for treatment with estramustine.

External beam radiotherapy of localized prostatic adenocarcinoma. Evaluation of conformal therapy, field number and target margins.

The purpose of the present study was to identify factors of importance in the planning of external beam radiotherapy of prostatic adenocarcinoma. Seven patients with urogenital cancers were planned for external radiotherapy of the prostate. Four different techniques were used, viz. a 4-field box technique and four-, five- or six-field conformal therapy set-ups combined with three different margins (1-3 cm). The evaluations were based on the doses delivered to the rectum and the urinary bladder. A normal tissue complication probability (NTCP) was calculated for each plan using Lyman's dose volume reduction method. The most important factors that resulted in a decrease of the dose delivered to the rectum and the bladder were the use of conformal therapy and smaller margins. Conformal therapy seemed more important for the dose distribution in the urinary bladder. Five- and six-field set-ups were not significantly better than those with four fields. NTCP calculations were in accordance with the evaluation of the dose volume histograms. To conclude, four-field conformal therapy utilizing reduced margins improves the dose distribution to the rectum and the urinary bladder in the radiotherapy of prostatic adenocarcinoma.

Field displacement during external radiotherapy in prostatic adenocarcinoma treated with radioactive 198Au implants and external irradiation.

The purpose of this work was to study displacement error and internal movements of the prostate during external beam radiotherapy. Verification films in the frontal (n = 194) and lateral (n = 64) portals were investigated in 14 patients treated with radioactive 198Au implants. Displacement errors of two implants were investigated. In seven patients, filling of the rectum and the bladder with contrast medium or isotonic saline was performed during CT investigation for planning purposes to detect movements of the prostate. Most (95%) of the displacement errors were less than 10 mm in the frontal portal and less than 15 mm in the lateral portals. No correlation to the patient's weight was found. The displacement errors were randomly distributed. The spatial relations between the implants were not altered during the treatments. Small movements of the prostate were observed. To conclude, the positioning system employed at present (laser) can be sufficient for the margins used (2 cm). In lateral portals, however, the system did not have the ability to detect a possible systematic displacement error from simulator to accelerator. The intention is to decrease the margins to 1 cm, which will necessitate a better positioning system.

Positron emission tomography utilizing C-11 5-hydroxytryptophan, plasma biochemistry and neuroendocrine immunohistochemistry of metastatic renal-cell carcinoma.

The aim of this study was to characterise metastatic renal cell carcinoma in 18 patients with positron emission tomography (PET) utilising C-11-5-hydroxytryptophan, plasma biochemistry and neuroendocrine immunochemistry. Of these 18 patients, ten underwent the PET investigations. The standardised uptake values (SUVs) in hepatic deposits were higher than those in pulmonary lesions, with mean values of 3.15 and 2.35, respectively. The immunohistochemical study included staining of 10/18 surgical tumour specimens with antibodies reactive with chromogranin (Cg), neurone-specific enolase (NSE), and synaptophysin (Sy). In 17/18 patients, plasma measurements of the neuroendocrine peptides, CgA, CgB, pancreastatin, and serotonin, were performed. The results obtained in this study show that PET with C-11-5-hydroxytryptophan, a precursor in serotonin synthesis in neuroendocrine cells, can be utilised to visualise primary renal cell cancer and its secondaries in vivo. The results obtained also suggest that neuroendocrine differentiation may occur in human RCC.

Positron emission tomography with L-methyl-11C-methionine in the monitoring of therapy response in muscle-invasive transitional cell carcinoma of the urinary bladder.

OBJECTIVE: To investigate whether positron emission tomography (PET) with L-methyl-11C-methionine as a tracer could be used for diagnostic purposes and for evaluation of therapy in patients with varying stages of urinary bladder cancer treated with chemotherapy. PATIENTS AND METHODS: PET was employed in 44 separate examinations involving 29 patients (24 men and five women with a median age of 68 years [mean 66, range 47-78]) with localized or metastatic transitional cell carcinoma of the urinary bladder. In four patients PET examinations were performed prior to the commencement of chemotherapy, and after one course and after three courses. RESULTS: The diagnostic accuracy of PET was poor. The technique did not monitor the therapeutic effect of neoadjuvant chemotherapy, producing results that correlated with therapy outcome. PET identified those patients who responded less successfully to therapy. CONCLUSION: PET with L-methyl-11C-methionine demonstrates alterations in tumour metabolism long before visible changes appear on computed tomography or magnetic resonance imaging. Further work is required to develop more specific tracers.

The efficacy of preoperative systemic chemotherapy in the local control of muscle-invasive transitional cell carcinoma of the urinary bladder.

Transitional cell carcinoma of the urinary bladder has a poor prognosis, once the muscle layers of the bladder wall have been invaded, irrespective of whether operative or radiation therapy is chosen for local treatment. The main reason for this is probably the existence of disseminated micrometastases at the time of primary treatment. Thus, a combination of systemic and local treatment would seem logical. The present study reports the response to chemotherapy in 30 patients with muscle-invasive urinary bladder tumours and the findings at subsequent cystectomy. The chemotherapy comprised cisplatin, methotrexate and leucovorin rescue and was tolerated without any alarming side-effects or increase in perioperative morbidity or mortality. The complete response rate was 43% (13/30) and, in 27% (8/30), there was a partial response with conversion into a more superficial tumour stage. The total, beneficial response rate was thus 70%.

Combined systemic chemotherapy and irradiation of muscle-invasive transitional cell carcinoma of the urinary bladder.

A phase II study is presented, which encompasses the period June 1987 until July 1993, and includes 53 patients with muscle-invasive bladder cancer T2-4b who, due to age and/or poor health (37 cases) or primarily extensive lesions (18 cases), were considered inoperable and for whom treatment with neoadjuvant chemotherapy (cisplatin/methotrexate/leucovorin rescue) and radical irradiation was planned. The total number of intended chemotherapy courses could be delivered without undue toxicity to 46 patients (83%) and 44 subsequently underwent radiotherapy: this modality was, by and large, well tolerated. The primary transurethral resection and chemotherapy produced an objective response in 62% of the 53 patients and in 75% of the 44 evaluable patients. The combined programme produced an objective response in 83% of the 37 evaluable patients, 71% in the 44 patients who completed the combined programme and in 59% of the total group of 53 patients. The follow-up ranged from 3 to 62 months. Radiotherapy increased the total objective response rate, proving effective in approximately 50% of patients who did not respond to chemotherapy. The results of this study are regarded as promising and pave the way for a phase III trial.

Characterization and uptake of radiolabelled meta-iodobenzylguanidine (MIBG) in a human neuroblastoma heterotransplant model in athymic rats.

Cells from an established human neuroblastoma cell line, SH-SY5Y, were demonstrated to grow and form solid tumours in nude rats. This cell line, which is an adrenergic subclone of the SK-N-SH cell line, has previously been used in differentiation model studies. The tumours retained the neuronal phenotype of the cultured cells, as evidenced by the expression of neuron-specific enolase (NSE) and chromogranin A + B. The transcription factor Isl-1, a protein expressed in subsets of neurons and endocrine cells as well as in neuroblastoma cells, was also expressed in the transplanted tumours, thus further verifying the retained phenotype of the cells under in vivo conditions. At scintigraphy utilizing 123I-MIBG the optimal tumour/background ratio was obtained 20 h after injection. The assessment of tissue/serum ratios showed the highest uptake in the spleen (0.067% per gram of inj. activity), neuroblastoma tumours (0.067% per gram of inj. activity) and in the adrenals (0.065% per gram of inj. activity).

Immunotargeting with monoclonal cytokeratin 8 antibodies of human urothelial cancer transplanted to nude mice.

The possibility of using cytokeratin antibodies for the radioimmunolocalization of urinary bladder cancer was studied. A monoclonal murine IgG antibody was raised against cytokeratin 8 and labelled with iodine-125; normal murine IgG was used for control purposes. The urothelial cancer cell line RT4 was transplanted into immunodeficient nude mice. The anti-cytokeratin 8 antibody was administered intraperitoneally and its uptake in the tumour and other organs was analyzed with a computerized gamma camera. Optimal scintigraphic visualization occurred 11 days after antibody administration. The tumour/blood ratio of the specific antibody was 5.64 (+/- 5.01 SD) on day 11, compared with 0.73 (+/- 0.35 SD) in the control. Autoradiography demonstrated antibody uptake preferentially in viable sections of the tumour. The antibody uptake is presumed to be the result mainly of binding to the released cytokeratin in and around cells lysed during natural cellular death. The monoclonal murine anti-cytokeratin antibody is of potential interest in studies aimed at improving the clinical staging of urinary bladder cancer.