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.

Metastatic renal cell carcinoma to the brain: optimizing patient selection for gamma knife radiosurgery.

INTRODUCTION: The effects of single-fraction gamma knife radiosurgery (sf-GKRS) on patients with renal cell carcinoma (RCC) brain metastases (BM) in the era of targeted agents (TA) and immune checkpoint inhibitors (ICI) are insufficiently studied. METHODS AND MATERIALS: Clear cell metastatic RCC patients treated with sf-GKRS due to BM in 2005-2014 at three European centres were retrospectively analysed (n = 43). Median follow-up was 56 months. Ninety-five percent had prior nephrectomy, 53% synchronous metastasis and 86% extracranial disease at first sf-GKRS. Karnofsky performance status (KPS) ranged from 60 to 100%. Outcome measures were overall survival (OS), local control (LC) and adverse radiation effects (ARE). RESULTS: One hundred and ninety-four targets were irradiated. The median number of targets at first sf-GKRS was two. The median prescription dose was 22.0 Gy. Thirty-seven percent had repeated sf-GKRS. Eighty-eight percent received TA. LC rates at 12 and 18 months were 97% and 90%. Median OS from the first sf-GKRS was 15.7 months. Low serum albumin (HR for death 5.3), corticosteroid use pre-sf-GKRS (HR for death 5.8) and KPS < 80 (HR for death 9.1) were independently associated with worse OS. No further prognostic information was gleaned from MSKCC risk group, synchronous metastasis, age, number of BM or extracranial metastases. Other prognostic scores for BM radiosurgery, including DS-GPA, renal-GPA, LLV-SIR and CITV-SIR, again, did not add further prognostic value. ARE were seldom symptomatic and were associated with tumour volume, 10-Gy volume and pre-treatment perifocal oedema. ARE were less common among patients treated with TA within 1 month of sf-GKRS. CONCLUSIONS: We identified albumin, corticosteroid use and KPS as independent prognostic factors for sf-GKRS of clear cell RCC BM. Studies focusing on the prognostic significance of albumin in sf-GKRS are rare. Further studies with a larger number of patients are warranted to confirm the above analytical outcome. Also, in keeping with previous studies, our data showed optimal rates of local tumour control and limited toxicity post radiosurgery, rendering GKRS the tool of choice in the management of RCC BM.

Adaptive radiosurgery based on two simultaneous dose prescriptions in the management of large renal cell carcinoma brain metastases in critical areas: Towards customization.

BACKGROUND: The long-term benefits of local therapy in metastatic renal cell carcinoma (mRCC) have been widely documented. In this context, single fraction gamma knife radiosurgery (SF-GKRS) is routinely used in the management of brain metastases. However, SF-GKRS is not always feasible due to volumetric and regional constraints. We intend to illustrate how a dose-volume adaptive hypofractionated GKRS technique based on two concurrent dose prescriptions termed rapid rescue radiosurgery (RRR) can be utilized in this particular scenario. CASE DESCRIPTION: A 56-year-old man presented with left-sided hemiparesis; the imaging showed a 13.1 cc brain metastasis in the right central sulcus (Met 1). Further investigation confirmed the histology to be a metastatic clear cell RCC. Met 1 was treated with upfront RRR. Follow-up magnetic resonance imaging (MRI) at 10 months showed further volume regression of Met 1; however, concurrently, a new 17.3 cc lesion was reported in the boundaries of the left frontotemporal region (Met 2) as well as a small metastasis (<1 cc) in the left temporal lobe (Met 3). Met 2 and Met 3 underwent RRR and SF-GKRS, respectively. RESULTS: Gradual and sustained tumor ablation of Met 1 and Met 2 was demonstrated on a 20 months long follow- up. The patient succumbed to extracranial disease 21 months after the treatment of Met 1 without evidence of neurological impairment post-RRR. CONCLUSION: Despite poor prognosis and precluding clinical factors (failing systemic treatment, eloquent location, and radioresistant histology), RRR provided optimal tumor ablation and salvage of neurofunction with limited toxicity throughout follow-up.

Overall survival after stereotactic radiotherapy or surgical metastasectomy in oligometastatic renal cell carcinoma patients treated at two Swedish centres 2005-2014.

BACKGROUND AND PURPOSE: Investigate effects of stereotactic radiotherapy (SRT) or surgical metastasectomy (SM) on overall survival (OS) in metastatic renal cell carcinoma (mRCC) in the era of targeted agents (TA). MATERIAL AND METHODS: mRCC patients (n = 117) treated with SRT (n = 57), SM (n = 30) or both modalities sequentially (n = 30) at two oncological centres in Sweden in 2005-2014 were retrospectively included. Median follow-up (mFU) was 63 months. RESULTS: A majority had clear cell histology, 1-3 metastases, and ECOG performance status of 0 or 1. Two thirds had intermediate or poor risk and 44% synchronous metastases. 65% received TA. SRT patients were more likely to have adverse risk profiles. Median OS was 51 months without significant differences between SRT and SM. ECOG 1 vs 0 (HR 2.9; CI 1.6-5.2; p < 0.001), intracranial targets (HR 1.8; CI 1.1-3.2; p = 0.03) and watchful waiting >18 months prior to treatment (HR 0.3; CI 0.2-0.6; p = 0.001) were independently associated with OS. 15% of curatively treated patients (n = 60) were relapse-free with mFU of 87 months. CONCLUSIONS: OS after SRT was comparable to SM and longer than expected considering patients with adverse risk profiles were common. Fit patients with non-brain metastases treated after an initial period of watchful waiting had the best prognosis.

Evaluation of third treatment week as temporal window for assessing responsiveness on repeated FDG-PET-CT scans in Non-Small Cell Lung Cancer patients.

PURPOSE: Early assessment of tumour response to treatment with repeated FDG-PET-CT imaging has potential for treatment adaptation but it is unclear what the optimal time window for this evaluation is. Previous studies indicate that changes in SUVmean and the effective radiosensitivity (αeff, accounting for uptake variations and accumulated dose until the second FDG-PET-CT scan) are predictive of 2-year overall survival (OS) when imaging is performed before radiotherapy and during the second week. This study aims to investigate if multiple FDG-PET-derived quantities determined during the third treatment week have stronger predictive power. METHODS: Twenty-eight lung cancer patients were imaged with FDG-PET-CT before radiotherapy (PET1) and during the third week (PET2). SUVmean, SUVmax, SUVpeak, MTV41%-50% (Metabolic Tumour Volume), TLG41%-50% (Total Lesion Glycolysis) in PET1 and PET2 and their change (), as well as average αeff (α¯eff) and the negative fraction of αeff values [Formula: see text] ) were determined. Correlations were sought between FDG-PET-derived quantities and OS with ROC analysis. RESULTS: Neither SUVmean, SUVmax, SUVpeak in PET1 and PET2 (AUC = 0.5-0.6), nor their changes (AUC = 0.5-0.6) were significant for outcome prediction purposes. Lack of correlation with OS was also found for α¯eff (AUC = 0.5) and [Formula: see text] (AUC = 0.5). Threshold-based quantities (MTV41%-50%, TLG41%-50%) and their changes had AUC = 0.5-0.7. P-values were in all cases ≫0.05. CONCLUSIONS: The poor OS predictive power of the quantities determined from repeated FDG-PET-CT images indicates that the third week of treatment might not be suitable for treatment response assessment. Comparatively, the second week during the treatment appears to be a better time window.

A phase I trial of DNA vaccination with a plasmid expressing prostate-specific antigen in patients with hormone-refractory prostate cancer.

Prostate-specific antigen (PSA) is a serine protease secreted at low levels by normal luminal epithelial cells of the prostate and in significantly higher levels by prostate cancer cells. Therefore, PSA is a potential target for various immunotherapeutical approaches against prostate cancer. DNA vaccination has been investigated as immunotherapy for infectious diseases in patients and for specific treatment of cancer in certain animal models. In animal studies, we have demonstrated that vaccination with plasmid vector pVAX/PSA results in PSA-specific cellular response and protection against tumour challenge. The purpose of the trial was to evaluate the safety, feasibility and biological efficacy of pVAX/PSA vaccine in the clinic. A phase I trial of pVAX/PSA, together with cytokine granulocyte/macrophage-colony stimulating factor (GM-CSF) (Molgramostim) and IL-2 (Aldesleukin) as vaccine adjuvants, was carried out in patients with hormone-refractory prostate cancer. To evaluate the biologically active dose, the vaccine was administered during five cycles in doses of 100, 300 and 900 microg, with three patients in each cohort. Eight patients were evaluable. A PSA-specific cellular immune response, measured by IFN-gamma production against recombinant PSA protein, and a rise in anti-PSA IgG were detected in two of three patients after vaccination in the highest dose cohort. A decrease in the slope of PSA was observed in the two patients exhibiting IFN-gamma production to PSA. No adverse effects (WHO grade >2) were observed in any dose cohort. We demonstrate that DNA vaccination with a PSA-coding plasmid vector, given with GM-CSF and IL-2 to patients with prostate cancer, is safe and in doses of 900 microg the vaccine can induce cellular and humoral immune responses against PSA protein.

Low-intensity conditioning and hematopoietic stem cell transplantation in patients with renal and colon carcinoma.

We have evaluated whether allogeneic hematopoietic stem cell transplantation (HSCT) could induce an antitumor effect in patients with metastatic solid tumors. A total of 12 HLA-identical siblings and 6 HLA-A-, -B- and -DR beta 1-compatible unrelated grafts were used. Diagnoses were adenocarcinoma of kidney (n=10), colon (n=6), breast (n=1) and cholangiocarcinoma (n=1). Conditioning was fludarabine 30 mg/m(2)/day for 3 days and 2 Gy of total body irradiation. Recipients of unrelated HSCT were also given thymoglobuline and two additional days of fludarabine. The median CD34+ cell dose was 7.5 x 10(6)/kg. Immunosuppression was mycophenolate mofetil and cyclosporin. Among all, 12 patients became complete donor chimeras within a median of 28, 29 and 65 days for B, myeloid and T cells, respectively. Two patients rejected the grafts, one developed marrow aplasia and three were mixed chimeras. The probability of grades II-IV acute graft-versus-host-disease (GVHD) was 57%. Regression of all tumor metastases was seen in one patient with colon carcinoma. Another patient with colon and two with renal carcinoma had regression of lung metastases, but progression of metastases in the liver and/or bone. Necrosis of lung metastasis was found in one further patient with renal carcinoma who died of graft-versus-host-disease (GVHD). In all, 10 patients died; four of transplant-related complications, one of trauma and five of progressive disease. Thus, progression was common after allogeneic HSCT in unselected patients with advanced solid tumors. However, the regression of some metastases associated with GVHD provides suggestive evidence that the GVHD effect may occur in renal and colon adenocarcinoma using reduced intensity conditioning.

Treatment with GM-CSF and IL-2 in patients with metastatic colorectal carcinoma induced high serum levels of neopterin and sIL-2R, an indicator of immune suppression.

Cytokines may enhance the effect of therapeutic monoclonal antibodies (mAb). Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) have been shown to increase ADCC levels. GM-CSF may augment the induction of an idiotypic network response (anti-tumour immunity). The clinical anti-tumour effect of a combination of mouse mAb17-1A-1A [anti-colorectal carcinoma (CRC)], and GM-CSF was, however, not enhanced by the addition of IL-2. In the present study, some immune functions considered to be involved in mAb-mediated tumour cell killing were analysed in patients receiving GM-CSF and GM-CSF/IL-2 respectively together with the mAb17-1A-1A. Ten patients received mAb17-1A and GM-CSF, and ten patients mAb17-1A with GM-CSF and IL-2. During a 10- day cytokine treatment period, a significantly higher increase in white blood cell counts was noted in the GM-CSF/IL-2 treatment group as compared to GM-CSF-treated patients. In the GM-CSF/IL-2 group, significantly higher serum concentrations of neopterin and soluble IL-2 receptor (sIL-2R) respectively were induced as compared to GM-CSF-treated patients. However, the ADCC of peripheral blood mononuclear cells (PBMC) against a CRC cell line was significantly higher in the GM-CSF group than in the GM-CSF/IL-2 group. The frequencies of patients developing human anti-mouse antibodies (HAMA) and anti-idiotypic antibodies were the same in both groups, while serum concentrations were significantly lower in the GM-CSF/IL-2 group as compared to the GM-CSF group. GM-CSF/IL-2 therapy seems to induce an immune suppressive stage compared to GM-CSF alone affecting cytotoxic mononuclear cells and B cells, which might be mediated through the neopterin metabolic pathway or other inducible immune suppressive factors such as reactive oxygen and nitrogen intermediates.

Outpatient treatment with subcutaneous histamine dihydrochloride in combination with interleukin-2 and interferon-alpha in patients with metastatic renal cell carcinoma: results of an open single-armed multicentre phase II study.

OBJECTIVES: Histamine inhibits formation and release of monocyte/macrophage-derived reactive oxygen metabolites and thereby protects natural killer (NK) and T cells against oxidative inhibition. Efficacy and safety of histamine, when given in combination with interleukin-2 (IL-2) and interferon-alpha (IFN-alpha), were evaluated in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Forty-eight mRCC patients were included. The self-administered, outpatient regimen included IFN-alpha, 3 MIU s.c., once daily for 1 week, followed by up to nine 4 week cycles of IFN-alpha, 3 MIU s.c., days 1-7, weeks 1-4; interleukin-2, 2.4 MIU/m2 s.c., b.i.d., days 1-5, weeks 1 and 2; and histamine dihydrochloride, 1 mg s.c., b.i.d. days 1-5, weeks 1-4. RESULTS: Forty-six patients were eligible. Forty-two patients were evaluable for response with four partial responses (9% of eligible patients, 10% of evaluable patients). Fifteen patients (36%) had stable disease. After subsequent surgery of residual tumours, three patients (7%) had no evidence of disease at 14+, 21+ and 21+ months. Median survival time for all patients was 16.3 months. One grade 4 toxicity (thrombocytopenia) was observed. Most frequent grade 3 toxicities were fatigue/malaise (26%), dyspnoe (11%), nausea (9%) and stomatitis (9%). Four patients discontinued due to treatment-related toxicity. There were no treatment-related deaths. CONCLUSIONS: The present combination of histamine with IL-2 and IFN-alpha. as self-administered outpatient therapy is a safe and well-tolerated regimen. However, histamine does not appear to add efficacy with respect to response in this low-dose schedule of IL-2 and IFN-alpha. Whether histamine might improve efficacy with higher doses of IL-2 and IFN-alpha requires further investigation.

Efficacy of epoetin beta on hemoglobin, quality of life, and transfusion needs in patients with anemia due to hormone-refractory prostate cancer--a randomized study.

OBJECTIVE: Erythropoietin is shown to be an effective treatment for anemia in various types of cancers, however only limited studies have evaluated its benefits in advanced hormone-refractory prostate cancer (HRPC). This multi-center study investigated the influence of 2 different doses of epoetin beta on quality of life, hemoglobin level, need for blood transfusion, and safety, in the treatment of anemia in patients with metastatic HRPC. MATERIALS AND METHODS: This study randomized 180 patients to receive either epoetin beta 1000 IU or 5000 IU subcutaneously 3 times per week for 12 weeks. Hemoglobin was evaluated at study start and 6 time-points during the study. Quality of life (QoL) was assessed by the European Organization for Research and Treatment of Cancer questionnaire, QLC-C30, before treatment start and after 6 and 12 weeks of treatment. Best supportive care and blood transfusions were given, if clinically indicated. Additional laboratory values and adverse events were followed for safety. RESULTS: Hemoglobin increased significantly (>20 g/l) in 43% in the high dose (HD) group and 25% in the low dose (LD) group in response to treatment. Levels were significantly higher in the HD group than the LD group (p < 0.001) after 8 and 12 weeks. QoL improved significantly if the increase in hemoglobin was >20 g/l. Significantly more patients in the LD group received blood transfusions than the HD group (p < 0.005). There were no differences between the groups regarding overall quality of life and fatigue. The treatment was well tolerated in both groups. CONCLUSIONS: Epoetin beta is shown to be safe and effective for the treatment of anemia in many patients with HRPC. It is found to improve QoL and physical functioning, and relieve fatigue symptoms, in many of these critically ill patients.

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.

Electrochemical treatment of tumours.

The electrochemical treatment (EChT) of tumours implies that tumour tissue is treated with a continuous direct current through two or more electrodes placed in or near the tumour. The treatment offers considerable promise of a safe, simple and relatively noninvasive anti-tumour therapy for treatment of localised malignant as well as benign tumours. Although more than 10,000 patients have been treated in China during the past 10 years, EChT has not yet been universally accepted. The reason for this is the lack of essential preclinical studies and controlled clinical trials. Uncertainties regarding the destruction mechanism of EChT also hinder the development of an optimised and reliable dose-planning methodology. This article reviews the collected Chinese and occidental experiences of the electrochemical treatment of tumours, alone and in combination with other therapies. The current knowledge of the destruction mechanism underlying EChT is presented along with different approaches towards a dose planning methodology. In addition, we discuss our view of different important parameters that have to be accounted for, if clinical trials are to be initiated outside of China.

Precancerous lesions in the kidney.

Renal cell carcinoma (RCC), although occurring less frequently than prostate and bladder cancer, is actually the most malignant urologic disease, killing >35% of affected patients. Therefore, investigation of the nature of premalignant lesions of the kidney is a relevant issue. Following the most recent histological classification RCC can be subdivided into four categories: conventional RCC; papillary RCC; chromophobe RCC; and collecting duct carcinoma. In contrast to many genitourinary malignancies, premalignant alterations in the kidney are scarcely described. Intratubular epithelial dysplasia has been recognized as the most common precursor of RCC. In analogy to prostatic intraepithelial neoplasia (PIN), the premalignant lesions of the kidney are described as high or low-grade renal intratubular neoplasia. In contrast, precancerous lesions have been described as part of the von Hippel-Lindau syndrome (VHL) where the evolution from a simple cyst to an atypical cyst with epithelial hyperplasia to cystic or solid conventional-type RCC is well documented. Finally, in the genesis of papillary RCC an adenoma-carcinoma sequence has been recognized with specific genetic changes. There are no data on the epidemiology of premalignant lesions of the kidney, but research into the etiology of RCC has been extended substantially. Familial and genetic factors are well documented in VHL disease, in hereditary papillary RCC, in the tuberous sclerosis complex and in familial RCC. Cigarette smoking and obesity are established risk factors for RCC. Hypertension or its medication has also been associated with an increased risk. Among dietary factors an inverse relation between risk and consumption of vegetables and fruit has been found. Occupational exposure to substances such as asbestos and solvents has been linked to an increased risk of RCC. Specific RCC variants have distinctive chromosome alterations and several genes have been implicated in the development of RCC. Loss of material from the 3p chromosome characterizes conventional RCC and the deletion of the VHL suppressor gene plays an important role in the genesis of this RCC variant. In contrast, numerical changes with trisomy of chromosomes 7 and 17 and loss of the sex chromosome are typical changes in papillary tumors, whereas papillary RCC have additional trisomies. Chromophobe RCC is characterized by loss of chromosomes with a combination of monosomies. Less consistent genetic alterations are associated with collecting duct carcinoma. The traditional treatment of RCC is surgery by radical or partial nephrectomy. The latter approach carries a risk of tumor recurrence as a result of unrecognized satellite lesions or premalignant lesions that might have been present at the time of surgery. However, the reported recurrence rates after partial nephrectomy are <1% and therefore the possible presence of premalignant disease does not alter the actual treatment strategy advocated. Although multifocality and bilateral occurrence of RCC are much more likely in cases of papillary RCC, biopsy of the renal remnant or contralateral kidney is not justified even in patients with this tumor type. Conversely, patients with RIN in a partial or radical nephrectomy specimen or in a renal biopsy taken for whatever reason should be subjected to closer follow-up with regularly repeated ultrasound. When an effective chemopreventive regimen becomes available it might be useful for patients with an inherited risk of RCC as well as in those who are at risk of tumor recurrence after intervention. Mass screening with the purpose of detecting RCC at its earliest stage is not recommended at the present time, but screening focused on certain risk groups can be advocated. Further research is needed to identify avoidable risks, develop effective chemoprevention and recognize patients at risk.

Clinical effects of monoclonal antibody 17-1A combined with granulocyte/macrophage-colony-stimulating factor and interleukin-2 for treatment of patients with advanced colorectal carcinoma.

Granulocyte/macrophage-colony-stimulating factor (GM-CSF) has previously been indicated to enhance the therapeutic effect of the anti-colorectal carcinoma mAb17-1A as well as to augment in vivo immune effector functions. In vitro interleukin-2 (IL-2) augmented GM-CSF-induced antibody-dependent cellular cytotoxicity, a mechanism considered to be of significance for the therapeutic effect of mAb. A treatment regimen was elaborated that combined mAb17-1A (400 mg at day 3 of a 10-day treatment cycle) with the simultaneous administration of GM-CSF (250 microgram/m(2) once daily) and IL-2 (2.4 x 10(6) U/m(2) twice daily) for 10 days. The treatment cycle was repeated once a month. Twenty patients with advanced colorectal carcinoma were included in the study. One patient obtained a partial remission and 2 patients stable disease for 7 and 4 months respectively. The median survival time from the start of mAb therapy was 8 months. Owing to allergic reactions, the planned mAb17-1A dose had to be reduced by repeated infusions. At the fourth treatment cycle only 25% received the planned mAb dose. In 3 patients the GM-CSF and IL-2 dose was reduced because of side-effects. The subjective tolerability of the treatment was considered good or acceptable in more than 80% of the patients. The increment in white blood cell subsets induced by the cytokines decreased by increasing number of courses. This particular regimen did not augment the therapeutic effect of mAb17-1A anticipated from in vitro data but rather hampered the clinical effect of the antibody. The reason for this is not clear but a possibility might be the induction of immune suppression in vivo resulting from an impaired human anti-(mouse Ab) and anti-idiotypic antibody response as well as antibody-dependent cellular cytotoxicity, on the basis of a comparison of mAb17-1A/GM-CSF/IL-2- and mAb17-1A/GM-CSF-treated patients.

Failures after operation for skeletal metastatic lesions of long bones.

This study was based on 192 patients treated surgically for 228 metastatic lesions of the long bones from 1986 through 1995. The survival rate was 0.3 at 1 year after surgery. The surgical treatment consisted of resection and reconstruction of the involved bone (18), intralesional curettage (133), or stabilization only (77). Reconstruction was achieved by an endoprosthesis in 54 cases, by an osteosynthetic device in 162, by cement only in 10. In two cases no reconstruction was performed. The local failure rate was 11% and the median time to failure was 8 months. Local failure was most frequent in patients with kidney cancer (24%) and in diaphyseal and distal femoral lesions (20%). Among 162 operations involving osteosynthetic devices, 22 (14%) were failures as compared with one of 54 (2%) endoprostheses. Sixty percent of the patients received preoperative or postoperative radiotherapy. Five of the six patients who had surgery for local tumor progression had not received radiotherapy. Eight of 10 nonunions and all five patients who developed a stress fracture had been treated with radiotherapy. It is concluded that endoprosthetic reconstructions are preferable to osteosynthetic devices. The skeletal complications associated with radiotherapy may be circumvented by the use of endoprostheses.

Angiostatin fragments in urine from patients with malignant disease.

Angiostatin, a family of fragments originating from the NH2-terminal portion of plasminogen, has been described as a potent inhibitor of angiogenesis. In order to examine to what extent angiostatin can be detected in cancer patients, urine was collected from 117 patients with different types of malignancies and subjected to Western blot analysis, utilizing antibodies raised against "kringles" 1-3 in plasminogen. A heterogeneous mixture of fragments was observed, with patterns that also varied between patients. Angiostatin fragments were quantified by densitometric scanning. The concentrations were 27 +/- 75 (SD) micrograms L-1 (range, 1-565 micrograms L-1) in urine from cancer patients, as compared to 3 +/- 2 (SD) micrograms L-1 (range, 1-10 micrograms L-1) in urine from healthy individuals. Thirty-three patients (28%) had elevated levels using a cut off level at 15 micrograms L-1 (clearly above the highest level obtained among control subjects). NH2-terminal amino acid sequence analysis of purified angiostatin fragments from one patient showed a heterogeneous pattern, but were consistent with the region between the preactivation peptide in plasminogen and "kringle" 1, as expected. Several of the patients with urinary angiostatin showed signs of poor kidney function. We conclude that angiostatin can be detected in urine from cancer patients, but at present, the clinical significance of this finding is unclear.

Survival in renal cell carcinoma-a randomized evaluation of tamoxifen vs interleukin 2, alpha-interferon (leucocyte) and tamoxifen.

Metastatic renal cell carcinoma (RCC) has a poor prognosis. Conventional treatment strategies, including chemotherapy and hormonal therapy, have limited value. Although encouraging results have been achieved in terms of objective response using immunological manipulations, no conclusive studies yet exist with a controlled comparative evaluation of survival. Therefore, the present study was undertaken, which compared one of the present (and presumed best) treatments, interleukin 2/interferon-alpha (IL-2/IFN-alpha) and tamoxifen, with a control arm of tamoxifen only. Tamoxifen has been shown to potentiate in vivo anti-tumour activity of IL-2, and because of its non-toxic behaviour it was included in both groups. The study was open, randomized and included seven institutions in Sweden. The patients were stratified according to the different centres involved. An interim analysis was planned when a minimum of 100 patients were evaluable. The 128 patients finally included had a histologically documented metastatic RCC, with a life expectancy of more than 3 months, a performance status WHO 0-2 and no prior chemo- or immunotherapy. Informed consent was obtained from each patient. The patients randomized to the control arm (n = 63) received only tamoxifen 40 mg p.o. daily for at least 1 year or until progression. The patients (n = 65) randomized to biotherapy received subcutaneous recombinant IL-2, leucocyte IFN-alpha in a treatment cycle of 42 days, as well as tamoxifen p.o. In the absence of undue toxicity or disease progression, these patients received one additional treatment cycle of 42 days followed by maintenance treatment, consisting of 5 days therapy every 4 weeks, for 1 year, or until proven progression. Only two patients in the tamoxifen-only group received immunotherapy when the disease progressed, but without any beneficial effect. All patients received appropriate local treatment when indicated. The interim analysis demonstrated no survival advantage for either group, and therefore further inclusion of patients was stopped. The median follow-up was 11 months (range 0.4-48 months). The final survival analysis showed no significant differences between the two treatment arms in so far as comparison from the day of diagnosis of primary disease, from the day of first evidence of metastatic spread, or from the onset of treatment. This was valid both when the evaluation was performed with regard to intention to treat and when the analysis was directed only to patients that managed at least one treatment cycle (42 days) of IL-2/IFN-alpha. The adverse effects were more pronounced in the IL-2/IFN-alpha group. Although the number of patients is limited, the results raise doubt concerning immunotherapy with IL-2 and IFN-alpha as a routine treatment in the management of advanced RCC. The difference in cost of drugs and health care (drug costs per patient: IL-2/IFN-alpha $27000 vs tamoxifen $360) as well as adverse effects caused by IL-2/IFN-alpha are also factors of importance. The study emphasizes the need for more effort to find the 'optimal schedule' of immunotherapy, as well as the need for randomized controlled studies before approval of a new treatment in the routine setting.

Induction of a T- and B-cell response against a unique amino acid sequence of the mouse IgG2A hinge region in a MAb-treated patient.

A patient with malignant glioblastoma was treated with intratumoral infusions of the murine MAb425 (IgG2A) directed against the epidermal growth factor receptor. At the 10th infusion, the patient developed somnolence, fever and headache. The symptoms increased during the subsequent 48 hr but then gradually disappeared within a week. The cerebrospinal fluid (CSF) contained increased concentrations of interleukin-2. The main CSF cell subset was CD4 T-cells. A marked blood lymphocyte proliferative response against mouse IgG2A was noted. The reactive T-cell epitope(s) could be localized to a 14 amino acid (RGPTIKPCPPCKCP) long peptide of the hinge region. A B-cell response (IgG antibodies) against this peptide was also induced.

Intratumoral infusion of the monoclonal antibody, mAb 425, against the epidermal-growth-factor receptor in patients with advanced malignant glioma.

Malignant glioblastoma may over-express the epidermal-growth-factor receptor (EGF-R). Normal brain cells show a low or no expression of EGF-R. A mouse monoclonal antibody (IgG2A) (mAb 425) (EMD55900) (Merck KGaA, Bernstadt, Germany) directed against EGF-R was produced for therapeutic use. Eight patients with primary or recurrent, EGF-R-positive glioblastomas entered the study, which was designed to evaluate the clinical effect of the mAb. In order to achieve a high tumor cell saturation, the mAb was injected intratumorally twice weekly through an implantable catheter. The total administered dose varied between 4 mg and 120 mg. In 3 patients with solid tumors, a massive tumor necrosis was noted, with infiltration of macrophages, granulocytes and T cells. A further 3 patients developed clinical and radiological signs of an intense, local, inflammatory reaction. There may be a relation between the mAb dosage and the antitumor effect, insofar as higher doses seemed to cause a more pronounced, inflammatory reaction. Of the 8 patients, 6 developed human, anti-(mouse Ig) antibodies. This anti-EGF-R mAb may induce an intense, inflammatory reaction and a considerable necrosis in glioblastoma. However, the planned schedule could not be completed, even after the dose level was re-adjusted, owing to inflammatory reactions, which were severe without prior tumor debulking.