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Each year, more than 1500 new cases of renal cell carcinoma are diagnosed in the Netherlands, and approximately 850 patients die due to this disease. The guideline 'Renal cell carcinoma' contains clinical practice recommendations on the diagnosis (imaging, pathological assessment, histopathological classification) and treatment (surgery, chemo-, immuno-, and radiotherapy) of renal cell carcinoma. For diagnostic imaging, chest and abdominal CT is recommended. Scintigraphy is not recommended. The term 'Grawitz tumour' is obsolete and should be replaced by 'renal cell carcinoma' with histological subtype specification according to the 2004 WHO classification. Laparoscopic radical nephrectomy is as effective as open surgery for localised tumours (T1 and T2) and possibly also for T3 tumours. The laparoscopic approach is associated with less morbidity due to the less invasive nature of this technique. This operation requires experience. In partial nephrectomy, a small margin of healthy tissue is sufficient. Frozen section examination of the resection edges does not appear to be required. In patients with metastatic renal cell carcinoma who are eligible for immunotherapy, removal of the tumour prolongs survival. Metastasectomy prolongs survival in patients with a solitary metastasis. Most currently available cytotoxic agents are ineffective against renal cell carcinoma. Interferon-alpha may have a role in the treatment of patients with renal cell carcinoma and favourable prognostic factors, given the survival advantage demonstrated with this agent in clinical trials. The guideline is available in English at www.oncoline.nl.

Treatment of patients with metastatic renal cell carcinoma is evolving rapidly due to the advent of novel targeted therapies. Improved knowledge of the underlying pathogenesis has led to the development of drugs that modulate the dominant signal transduction pathways for this disease, which results in inhibition of angiogenesis. Recent evidence indicates that the receptor tyrosine kinase inhibitor sunitinib prolongs progression-free survival compared with interferon-alpha, especially in patients with intermediate risk. Immunotherapy with interferon-alpha or high-dose interleukin-2 should still be considered for low-risk patients, particularly those with clear-cell tumours and metastases of the lung only. In patients who fail treatment with interferon-alpha, sorafenib has been shown to improve progression-free survival. High-risk patients may benefit from treatment with temsirolimus, which inhibits mammalian target of rapamycin (mTOR) kinase activity and has shown to improve overall survival. These angiogenesis inhibitors did not receive mention in the recently published guideline 'Renal cell carcinoma'.

In Europe, renal cancer (that is neoplasia of the kidney, renal pelvis or ureter (ICD-9 189 and ICD-10 C64-C66)) ranks as the seventh most common malignancy in men amongst whom there are 29,600 new cases each year (3.5% of all cancers). Tobacco, obesity and a diet poor in vegetables are all acknowledged risk factors, along with specific occupational and environmental factors. A familial history of renal carcinoma is also likely to increase the risk. Renal carcinoma may remain clinically occult for most of its course. The classic presentation of pain, haematuria, and flank mass occurs in only 9% of patients and is often indicative of advanced disease. Approximately 30% of patients with renal carcinoma present with metastatic disease, 25% with locally advanced renal carcinoma and 45% with localized disease. Metastases are typically found in the lung, soft tissue, bone, liver, cutaneous sites, and central nervous system. The most important staging technique is a computed tomography (CT) scan of the whole abdomen. Survival rates are more favourable for patients with tumours confined to the kidney. Five-year survival for patients with metastatic renal carcinoma is comprised between 0 and 20%. Radical nephrectomy is the standard intervention for renal cancer. Intrinsic resistance to chemotherapy has long been a hallmark of renal carcinoma. Limited options are available for the systemic therapy, and no chemotherapeutic regimen is accepted as a standard of care. Biologic agents represent the major effective therapies for widespread metastatic renal cancer. An antiangiogenic strategy, the neutralization of VEGF, can slow the growth rate of advanced cancer.

With the emergence of novel angiogenesis inhibitors, we are moving to a new era for patients with metastasized renal cell carcinoma. Since the results achieved reflect more a modification of the natural course of the disease than a cure, past achievements should not be neglected. Low-risk patients with clear cell histology, especially those with pulmonary metastasis only, should still be offered cytokine therapy. For intermediate-risk patients sunitinib is the treatment of choice. For high-risk patients, temsirolimus has to date provided the most convincing data, its availability is however limited. Data with sorafenib and sunitinib in the high-risk group are still anecdotal. The toxicity profiles of these 2 drugs are different and might particularly relate to patients with known cardiovascular co-morbidity. No sufficient data are available regarding sequential use. After cytokine failure, sorafinib is the treatment of choice. Patients should preferably be treated within clinical trials to answer unaddressed questions. It is well known that the strict entry criteria used within the clinical studies were applied very flexibly when drugs have been approved. These aspects require a careful follow-up to ascertain optimal use and to prevent misuse. Finally, the costs of prolonged treatment will be enormous, and only meaningful survival advantages will convince the health authorities to make these new treatments available for all patients.

The mainstay of any curative treatment in renal cell carcinoma (RCC) is surgery. In the case of metastatic disease at presentation, a radical nephrectomy is recommended to good performance status patients prior to the start of cytokine treatment. Interferon (IFN)-a offers in a small but significant percentage of patients advantage in overall survival. Interleukin (IL)-2-based therapy gives similar survival rates. To date, hormonal therapy and chemotherapy do not have a proven impact on survival. Recent insights demonstrate that the majority of clear cell RCC harbor abnormalities of the von Hippel-Lindau (VHL) gene. This gene plays a key role in the stimulation of angiogenesis by vascular endothelial growth factor (VEGF) in this highly vascularized tumor. This opens interesting new treatment strategies including blockade of VEGF with the monoclonal antibody bevacizumab (Avastin) and inhibition of VEGF receptor tyrosine kinases with small oral molecules such as sunitinib (SU11248, Sutent) or PTK787. Likewise, inhibition of the Raf kinase pathway with oral sorafenib (Bay 43-9006, Nexavar) or inhibition of the mTOR pathway with intravenous CCI-779 are under investigation. Preliminary clinical results with all these compounds are promising, and the results of ongoing first-line phase III studies will become available in the next years.

Renal cell carcinoma (RCC) presents as localized disease in 54% of the cases. For these patients, surgery is the primary curative treatment. Unfortunately, up to 65% of all patients show recurrent disease. For metastatic RCC non-specific immunotherapy is currently the treatment of choice. Nevertheless, several new modalities, e.g. WX-G250, oncophage and anti-angiogenic compounds like sunitinib and sorafenib are being explored with favorable results. Still, their place in the primary treatment of advanced RCC has yet to be determined. Because of the high percentage of recurrent disease, there is a need to identify these patients with conventional and molecular risk factors. Furthermore, adjuvant therapy to reduce risk of recurrence of RCC following nephrectomy is of clinical relevance. A review of recent literature was performed on the topics prognostic models, risk factors and adjuvant treatment for non-metastasized RCC. Combining classical risk factors for progression of RCC has shown to be effective for stratifying patients into risk groups. The UCLA integrated staging system (UISS) is the currently the only validated prognostic model. Whether molecular markers are able to better identify high-risk patients is still under investigation. Adjuvant therapy has been explored in the treatment for RCC and the use of non-specific cytokine regimens has so far not shown to be effective in the adjuvant setting. More specific therapies, e.g. WX-G250, oncophage and anti-angiogenic drugs are clinically active in patients with advanced RCC. Large randomized clinical trials with these drugs are currently ongoing to evaluate their effect in patients with localized RCC.

Purpose: A study was designed to define the therapeutic efficacy, safety, and toxicity of two sequential high-dose treatments of radioimmunotherapy with [131I]cG250 in patients with metastasized renal cell carcinoma. Here, we report the dosimetric analysis and the relationship between the development of a human antichimeric antibody response and altered pharmacokinetics., Experimental Design: Patients (n = 29) with progressive metastatic renal cell carcinoma received a low dose (222 MBq) of [131I]cG250 for dosimetric analysis, followed by the first radioimmunotherapy with 2,220 MBq/m2 [131I]cG250 (n = 27) 1 week later. If no grade 4 hematologic toxicity was observed, a second low dose of [131I]cG250 (n = 20) was given 3 months later. Provided that no accelerated blood clearance was observed, a second radioimmunotherapy of [131I]cG250 was administered at an activity-dose level of 1,110 MBq/m2 (n = 3) or 1,665 MBq/m2 (n = 16). After each administration, whole-body images were obtained and the pharmacokinetics and the development of human antichimeric antibody responses were determined. Radiation-absorbed doses were calculated for whole body, red marrow, organs, and metastases., Results: No correlation was found between hematologic toxicity and radiation-absorbed dose to the whole body or bone marrow, nor administered activity (MBq and MBq/kg). The tumor-absorbed doses varied largely. An inverse relation between tumor size and radiation-absorbed dose was found. Most tumor lesions received <10 Gy, whereas only lesions <5 g absorbed >50 Gy. A relatively high number of patients developed a human antichimeric antibody response (8 of 27) with altered pharmacokinetics, hampering additional radioimmunotherapies in four of these patients., Conclusions: Dosimetric analysis did not adequately predict the degree of bone marrow toxicity. When human antichimeric antibody developed, the rapid clearance of radioactivity from the blood and body prohibited further treatment. According to the calculated absorbed dose in metastatic lesions, future radioimmunotherapy studies with radiolabeled cG250 should aim at treatment of small-volume disease or treatment in an adjuvant setting.

Purpose: A previous activity dose-escalation study using 131I-labeled chimeric monoclonal antibody cG250 in patients with progressive metastatic renal cell carcinoma (RCC) resulted in occasional therapeutic responses. The present study was designed to determine the safety and therapeutic efficacy of two sequential high-dose treatments with 131I-cG250., Patients and Methods: Patients (n = 29) with progressive metastatic RCC received a low dose of (131)I-cG250 for assessment of preferential targeting of metastatic lesions, followed by the first radioimmunotherapy (RIT) with 2220 MBq/m2 131I-cG250 (n = 27) 1 week later. If no grade 4 hematologic toxicity was observed, a second low-dose 131I-cG250 (n = 20) was given 3 months later. When blood clearance was not accelerated, a second RIT of 131I-cG250 was administered at an activity-dose of 1110 MBq/m2 (n = 3) or 1665 MBq/m2 (n = 16). Patients were monitored weekly for toxicity, and tumor size was evaluated by computed tomography once every 3 months intervals., Results: The maximum-tolerated dose (MTD) of the second RIT was 1,665 MBq/m2 because of dose-limiting hematological toxicity. Based on an intention-to-treat analysis, after two RIT treatments, the disease stabilized in five of 29 patients, whereas it remained progressive in 14 of 29 patients. Two patients received no RIT, and eight of 29 received only one 131I-cG250 RIT because of grade 4 hematologic toxicity, formation of human antichimeric antibodies, or disease progression., Conclusion: In patients with progressive end-stage RCC, the MTD of the second treatment was 75% of the MTD of the first RIT. In the majority of patients, two cycles of 131I-cG250 could be safely administered without severe toxicity. No objective responses were observed, but occasionally two RIT doses resulted in stabilization of previously progressive disease.

The mainstay of any curative treatment in renal cell carcinoma (RCC) is surgery. In case of metastatic disease at presentation a radical nephrectomy is recommended to good performance status patients prior to start of interferon-alfa treatment. Interferon-alpha (IFN-alpha) offers in a small but significant percentage of patients advantage in overall survival; interleukin-2 (IL-2) based therapy gives similar survival rates. To date hormonal and chemotherapy do not have a proven impact on survival. The recent new insights in the molecular biology of clear RCC has revealed a key-role for vascular endothelial growth factor (VEGF) in the stimulation of angiogenesis in this highly vascularized tumour. This opens interesting new treatment strategies including: blockage of VEGF with the monoclonal antibody bevacizumab and inhibition of VEGF receptor tyrosine kinases (with small oral molecules such as SU11248 or PTK787). Likewise, inhibition of the Raf kinase pathway (with oral Bay 43-9006) or inhibition of the mTOR pathway (with i.v. CCI-779) are under investigation. Preliminary clinical results with all these compounds are interesting and the results of ongoing phase III studies will become available in the next years.

Metastatic renal-cell carcinoma (mRCC) is highly resistant to cytotoxic agents or hormones and is currently mainly treated with cytokine-based therapy. Transient responses and moderate survival advantages have been achieved in a subset of patients with these aspecific biological response modifiers. Side-effects are considerable, especially with high-dose interleukin (IL)-2. Efforts made in the field of specific immunotherapy have focused on optimization of dendritic cell vaccination and on administration of monoclonal antibodies, either cold (unconjugated) or hot (radioactively labeled). Furthermore, allogeneic bone marrow transplantation is able to induce remissions but, regrettably, is related to substantial morbidity and mortality. Neutralization of the biological activity of some immunosuppressive cytokines produced by RCC (IL-6 and tumor necrosis factor-alpha) with monoclonal antibodies is currently under investigation. Insights gained into the processes and pathways underlying carcinogenesis have led to the development of new treatment strategies. These treatments can be used for clear cell RCC, since they focus on blocking gene products that are upregulated by mutations in the von Hippel-Lindau gene. Specific strategies include anti-vascular endothelial growth factor monoclonal antibody (bevacizumab) or inhibition of its receptor kinases (oral SU11248 or PTK787), or targeting the Raf kinase pathway (by BAY 43-9006) or the mammalian target of rapamycin (mTOR) pathway (by CCI-779). Early clinical results are promising, but their place in the treatment of RCC has to be determined.

Purpose: A randomized phase II/III trial was conducted to determine whether combination treatment with 13-cis-retinoic acid (13-CRA) plus interferon alfa-2a (IFN-alpha-2a) was superior to IFN-alpha-2a alone in patients with progressive metastatic renal cell carcinoma., Patients and Methods: Three hundred twenty patients were randomly assigned to treatment with IFN-alpha-2a plus 13-CRA or to IFN-alpha-2a alone. IFN-alpha-2a was given daily subcutaneously, starting at a dose of 3 million units (MU). The dose was escalated every 7 days from 3 to 9 MU by increments of 3 MU. Patients randomly assigned to combination therapy received oral 13-CRA 1 mg/kg/d plus IFN-alpha-2a., Results: Median time to progression was 5.1 months for patients treated with the combination and 3.4 months for patients on IFN-alpha-2a alone (P = .008). Progression-free survival rates at 6 months were 43% for patients receiving combined therapy and 30% for patients on IFN-alpha-2a, and at 12 months, 27% and 17%, respectively. Median overall survival was 17.3 months for patients on IFN-alpha-2a and 13-CRA, and 13.2 months for patients treated with IFN-alpha-2a (P = .048). Twenty-two percent of the patients receiving the combination stopped treatment due to toxicity, as compared with 16% on IFN-alpha-2a., Conclusion: Progression-free and overall survival for patients with progressive metastatic renal cell carcinoma treated with IFN-alpha-2a plus 13-CRA were significantly longer compared with patients on IFN-alpha-2a alone (P = .007 and P = .048, respectively). Improvement in efficacy in the combination arm was accompanied by increased, though not serious, toxicity.

Background: In patients with metastatic renal cell carcinoma (MRCC), interferon-alpha (IFN) monotherapy leads to response rates of 5-15%, dependent on the selection of patients. In 1995, preclinical and clinical data indicated an improvement of these results if IFN was combined with 13-cis retinoic acid (CRA)., Methods: In a randomized Phase II study, patients with measurable MRCC received either subcutaneous IFN (9 MU daily; Arm A) or the same daily subcutaneous dose of IFN plus oral CRA (1 mg/kg; Arm B). A central expert panel reviewed the X-ray documentation of objective responses., Results: In the 50 eligible patients from Arm A, the objective, expert-reviewed response rate was 6% (95% confidence interval [95% CI], 1.3-16.6%; 2 complete responses [CRs] and 1 partial response [PR]). A 19% response rate (95% CI, 9.4-32.0%) was stated for 53 eligible patients from Arm B (2 CRs and 8 PRs). Only one of the four CRs claimed by the clinical investigator was confirmed by the central review committee. Conversely, the expert committee deemed that 3 of 12 investigator-stated PRs were CRs. Constitutional toxicity (flu-like symptoms) and/or side effects from skin, mucosa, or eyes led to discontinuation of treatment in 22% of nonprogressing patients, more often in Arm B than in Arm A., Conclusions: The results from this randomized Phase II study support expansion of the trial into a Phase III study to evaluate the effect of IFN-CRA combination therapy on the survival of patients who undergo nephrectomy prior to IFN-based immunotherapy. The considerable interobserver variability of response evaluation (individual investigator vs. expert panel) indicates the necessity of a central review of claimed responses in future Phase II studies involving patients with MRCC.

Renal cell carcinoma was diagnosed in three male patients, 45, 53 and 52 years of age. In addition, they had paraneoplastic symptoms: hypercalcaemia, hyperglycaemia and elevated hepatic enzyme levels, respectively. All three patients underwent tumour nephrectomy, after which the paraneoplastic symptoms disappeared. The first patient died 16 months postoperatively, while the other two were alive and free of symptoms after a follow-up of nine months and four years, respectively. Many patients with renal cell carcinoma remain asymptomatic for a long period of time and 30% of all patients have metastatic disease at the time of diagnosis. The classic triad of flank pain, haematuria and an abdominal mass occurs in only 10% of all cases. However, 20-40% of all patients present with signs of a paraneoplastic syndrome, of which anaemia (20-40%), fever (30%), hypertension (24%), hypercalcaemia (10-15%) and hepatic dysfunction (3-6%) are the most common.

Purpose: There is increasing evidence that the chimeric monoclonal antibody G250 (cG250) can be internalized by G250 antigen-expressing renal cell carcinoma (RCC) cells. Thus, accumulation in tumors of cG250 labeled with residualizing radionuclides might be higher than that of nonresidualizing (131)I-cG250. Here, we present a study comparing intrapatiently the accumulation of (131)I-cG250 and (111)In-cG250 in RCC metastases., Experimental Design: Five patients were i.v. injected with 222 MBq (111)In-ITC-DTPA-cG250 and 222 MBq (131)I-cG250 on days 0 and 4, respectively. Directly and 4 days after the injection of both antibody preparations, whole body gamma camera images were acquired. The scintigraphic images were analyzed visually and quantitatively. The radioactivity in tissues was calculated and expressed as percentage injected dose in organs or percentage injected dose/g in metastases. For the latter, tumor:blood ratios were also calculated. Twenty-five metastases were analyzed completely., Results: At 4 days postinjection, the (111)In-ITC-DTPA-cG250 images revealed more metastatic lesions (n = 47) than (131)I-cG250 (n = 30). Quantitative analysis of the images showed higher activities of (111)In-ITC-DTPA-cG250 than (131)I-cG250 in 20 of 25 lesions. The mean overall half-life of both antibody preparations in plasma was similar., Conclusions: (111)In-ITC-DTPA-cG250 outperformed (131)I-cG250 for visualization of metastatic RCC lesions, not just because of the superior gamma camera characteristics of (111)In, but more importantly, also because higher tumor:blood ratios were obtained. The higher activities of (111)In-ITC-DTPA-cG250 in metastatic lesions might be caused by internalization and subsequent intracellular retention of the radiolabel, implying that in future radioimmunotherapy trials with cG250 in RCC patients, the use of a residualizing radionuclide should be considered.

Dendritic cells (DC) have been recognized as the most potent antigen presenting cells (APC) of the immune system. We performed a phase 1 study in twelve patients with metastatic renal cell carcinoma (RCC) using autologous immature DC loaded with autologous tumorlysate (TuLy) as a vaccine based on our earlier in vitro observations that such DC can activate tumor-specific cytotoxic T-lymphocytes. The treatment was combined with low-dose interleukin (IL)-2, as this has shown benefit in DC-based therapies. Patients received three intradermal vaccinations at two weekly intervals, and, after each vaccination, IL-2 was administered for 5 consecutive days. In six patients, keyhole-limpet hemocyanin (KLH) was added to the DC culture for immunologic monitoring purposes. In general, DC phenotype was CD14(low), CD86(high), CD40(high), CD80(low), and CD83(low). We noticed that the number of CD14+ cultured DC increased during treatment. Nevertheless, ovalbumin uptake remained high, underlining that these cells were still functional immature DC. The vaccine was able to elicit cellular anti-KLH responses, emphasizing the ability of the injected DC to mount an immunologic response. However, proliferative responses against TuLy were not detected, and humoral responses against TuLy or KLH were absent. Objective clinical responses were not observed, but extended stable disease was noted. The absence of cellular, humoral, or clinical antitumor responses suggests that the vaccination strategy with immature DC has little benefit for patients with advanced RCC. Nevertheless, this study shows the feasibility of a completely autologous DC and tissue culture methodology for the generation of TuLy pulsed DC.

Metastatic renal cell carcinoma has a poor prognosis. The value of immunotherapy with IFN-alpha and IL-2 both as single agent or as the combination is extensively investigated. The optimal dose and schedule is not known. In various studies response rates vary between 10 and 40%. The duration of response is variable. For a partial response a median duration between 10 and 12 months is given. Complete responses are sometimes long-lasting (a couple of years). The toxicity is drug, dose and schedule dependent. On the basis of a number of prognostic factors, such as performance score, time between the initial diagnosis and the treatment of metastases and the number of metastatic sites, patients can be divided in different prognostic groups. Patients who are classified in the good or intermediate prognostic group may have an improvement of their survival after immunotherapy and therefore they are candidates for immunotherapy.

After nephrectomy for renal cell carcinoma (RCC), a significant number of patients develop recurrent disease. In order to improve the prognosis of these patients, the role of adjuvant immunotherapy should be clarified; the appropriate selection of patients is especially crucial. For this purpose, the search for prognostic factors is important to identify at-risk patients. Known factors such as stage, grade, and microvascular invasion can be used for appropriate selection. Other molecular markers, such as cadherin-6 and G250 antigen, may become important. So far, adjuvant immunotherapy in RCC has not shown improved survival data, but the results may be hampered by inadequate recruitment and follow-up. Adequate selection of patients and the search for less toxic and more effective immunotherapy approaches are of importance. Therefore, the use of monoclonal antibody G250 or dendritic cell vaccinations, alone or together with cytokines, may be advantageous and is currently used. Today, adjuvant protocols are open for recruitment of patients to elucidate the important question as to whether this approach should be implemented in the treatment of RCC. In this article, an update is given in the field of adjuvant immunotherapy in patients with RCC.

In patients with metastatic renal cell carcinoma response rates of 7-26% have been achieved with immunotherapy. A high response rate of 48% in 35 patients has been reported for treatment with the combination of interferon-alpha (IFN-alpha), interleukin-2 (IL-2) and 5-fluorouracil (5-FU) (Atzpodien et al (1993a) Eur J Cancer29A: S6-8). We conducted a multicentre phase II study to confirm these results. Metastatic renal cell carcinoma patients were treated as outpatients with an 8-week treatment cycle. Recombinant human IL-2 20 MU m(-2) was administered subcutaneously (s.c.) three times a week (t.i.w) in weeks 1 and 4 and 5 MU m(-2) t.i.w. in weeks 2 and 3. Recombinant human IFN-alpha 2a 6 MU m(-2) was administered s.c. once in weeks 1 and 4 and t.i.w. in weeks 2 and 3, and 9 MU m(-2) t.i.w. in weeks 5-8. 5-FU (750 mg m(-2)) was given as a bolus injection intravenous once a week in weeks 5-8. The treatment cycle was repeated once in case of response or minor response. Fifty-two patients entered the study. All had undergone a nephrectomy and had progressive metastatic disease. The median WHO-performance status was 1, the median number of metastatic sites was 2 (range 1-5) and the median time between the diagnosis of the primary tumour and the start of treatment was 12.9 months (range 1-153). Among the 51 patients, including four patients with early progressive disease, who were evaluable for response, the response rate was 11.8% (95% confidence interval (CI) 2.9-20.7%), with no complete responses. Median duration of response was 8.3 (range 3.8-22.4+) months. Median survival was 16.5 (range 1.8-30.5+) months. Grade 3/4 toxicity (WHO) occurred in 29/52 (55.8%) of the patients in cycle 1 and in 6/16 (37.5%) of the patients in cycle 2. It consisted mainly of anorexia, fatigue, nausea, fever and leucocytopenia. We cannot confirm the high response rate in patients with metastatic renal cell carcinoma treated with the combination of IFN-alpha, IL-2 and 5-FU, as described by Atzpodien et al.

Clinical tumor targeting studies with chimeric monoclonal antibody G250 (cG250) in renal cell carcinoma (RCC) patients indicated the potential use of this antibody for radioimmunotherapy. Here we report on a phase I activity dose escalation study to determine the safety, the maximum tolerable dose (MTD), and the possible therapeutic potential of 131I-labeled cG250 in patients with progressive metastatic RCC. All patients (n = 12) received a diagnostic i.v. infusion of 5 mg of cG250 labeled with 222 MBq of 131I. If accumulation of the antibody in metastatic lesions was observed, patients were hospitalized and a second, therapeutic, i.v. infusion of 5 mg of cG250 labeled with a high dose of 131I was administered (n = 8). Three patients per dose level were entered, starting at 1665 MBq/m2. If no dose-limiting toxicity occurred, the study continued at the next dose level (555 MBq/m2 increase). Most patients experienced mild nausea without vomiting. No other complaints were reported during hospitalization. In two of two patients who received a dose of 2775 MBq/m2, grade IV hematological toxicity was observed, which was defined as dose limiting. Thus, the MTD was set at 2220 MBq/m2. In one patient (2220 MBq/m2), stable disease (lasting 3-6 months) was achieved, whereas another patient (2220 MBq/m2) showed a partial response that is ongoing (>9 months). The minor responses observed in this phase I trial in patients with an advanced stage of RCC are encouraging and warrant further study in a phase II setting at the MTD to determine the efficacy of radioimmunotherapy for metastatic RCC.

Metastatic renal cell carcinoma has a poor prognosis. The efficacy of immunotherapy with interferon alpha (IFN-alpha) or interleukin 2 (IL-2) or their combination has been investigated extensively. The best schedule and optimum dose and combination is not known. On the basis of three prognostic factors, viz. WHO performance score, time between initial diagnosis and treatment of metastases, and number of metastatic sites, patients can be divided in prognostic groups. Patients classified in the favourable or intermediate prognostic group may survive longer after immunotherapy and therefore are candidates for such therapy. Patients who are classified in the poor prognostic group will not profit from any known systemic therapy.

Following a previous EORTC GU-Group study, in which linomide showed some activity in poor prognosis patients, this study was initiated to determine the effect of linomide in more favourable patients. 35 patients with metastatic renal cell carcinoma with good prognostic factors, i.e. good performance status, prior nephrectomy, no prior systemic therapy, and no liver, bone or brain metastases, were treated with linomide, a quinoline derivative with immunomodulating properties, at a dose of 10 mg daily, after an initial dose escalation during the first 4 weeks of treatment. In 29 evaluable patients, no responses were observed (95% confidence interval 0-10%). Best overall response was no change in 9 patients, for a median duration of 4 months. Linomide in this schedule was poorly tolerated, with 17% (6 patients) of patients being withdrawn and 23% (8 patients) having dose reductions due to adverse events, mostly influenza-like symptoms of myalgia, arthralgia and fatigue. Several cases of pericarditis and neuropathy were observed. In spite of selection of favourable prognosis patients and an optimal daily dosing schedule, linomide was not an effective treatment in renal cell carcinoma. In view of toxicity and lack of efficacy, there is no rationale in further testing the drug in this disease.

The aim of this study was to determine the objective tumour response rate and duration of response and toxicity of linomide (Roquinimex) treatment in patients with disseminated renal cell carcinoma, pretreated or not pretreated with immunotherapy. From March 1991 to July 1992, 72 patients with metastatic and progressive renal cell cancer were entered of whom 9 (12%) were not evaluable for response. Linomide was given orally, twice weekly, 5 mg during the first week with dose escalation to 10 mg during the second week and 15 mg thereafter. Treatment was continued until disease progression or unacceptable toxicity. No haematological toxicity but slight anaemia was observed. A significant WBC (white blood cell count) increase (P < 0.0001, paired T-test) was found during treatment. The most often reported non-haematological side-effects were: flu-like syndrome (54%, grade III-IV 7%), nausea/vomiting (41% and 3%, respectively) and neurotoxicity (34% and 2%). Most side-effects were of mild or moderate intensity (WHO grade 1 or 2). The objective overall response rate was 4%: 1 CR and 2 PRs. Stable disease was reported for 28 patients (40%). The duration of response was 17, 22 and 30 (CR) months. Median time to progression was 5 months. Linomide at the given dose and schedule is well tolerated, but has limited antitumour activity in metastatic renal cell carcinoma.

S9788 is a new triazineaminopiperidine derivate capable of reversing multidrug resistance (MDR) in cells resistant to chemotherapeutic agents such as doxorubicin. It does not belong to a known class of MDR revertants, but its action involves the binding of P-glycoprotein. Thirty-eight evaluable patients with advanced colorectal or renal cell cancer were treated with doxorubicin alone (16 patients) followed after disease progression with combination treatment of doxorubicin plus S9788 (12 patients) or upfront with the combination of doxorubicin plus S9788 (22 patients). S9788 was given i.v. as a loading dose of 56 mg m-2 over 30 min followed by doxorubicin given at 50 mg m-2 as a bolus infusion. Thereafter, a 2-h infusion of S9788 was administered at escalating doses ranging from 24 to 120 mg m-2 in subsequent cohorts of 4-10 patients. Pharmacokinetic analysis demonstrated that concentrations of S9788 that are known to reverse MDR in vitro were achieved in patients at non-toxic doses. Compared with treatment with doxorubicin alone, treatment with the combination of doxorubicin and S9788 produced a significant increase in the occurrence of WHO grade 3-4 granulocytopenia. Treatment with S9788 was cardiotoxic as it caused a dose-dependent and reversible increase in corrected QT intervals as well as clinically non-significant arrhythmias on 24- or 48-h Holter recordings. Although clinically relevant cardiac toxicities did not occur, the study was terminated as higher doses of S9788 may increase the risk of severe cardiac arrhythmias. Twenty-nine patients treated with S9788 plus doxorubicin were evaluable for response, and one patient, who progressed after treatment with doxorubicin alone, achieved a partial response. We conclude that S9788 administered at the doses and schedule used in this study results in relevant plasma concentrations in humans and can safely be administered in combination with doxorubicin.

Preclinical and clinical studies have been performed to evaluate the efficacy of gemcitabine (2',2'-difluorodeoxycytidine; dFdC) in human renal cell carcinoma. Experimental data corroborated dFdC as an effective drug against cell lines from renal cell carcinomas (ACHN, A-498, SN12C) at concentrations much below clinically achievable doses. ACHN-bearing nude mice showed an overall response rate of 27% to dFdC (3 mice with complete response, 1 with partial response, 3 with stable and 8 with progressive disease). Objective response from 37 evaluable patients was 8.1% (1 patient with complete response and 2 patients with partial response). Gemcitabine was well tolerated thus, although gemcitabine at the dosage and schedule chosen had only small activity, the observed toxicity may permit further dose escalation or a more frequent administration of the drug.

A phase II trial investigating the anti-tumour effects of recombinant human interleukin 6 (rhIL-6) in patients with metastatic renal cell cancer was carried out. RhIL-6 (150 microgram) was administered as a daily subcutaneous injection for 42 consecutive days on an outpatient basis. Forty-nine patients were studied, 12 with and 37 without previous immunotherapy. Forty patients were evaluable for response. A partial remission was noted in two patients, stable disease in 17 and progressive disease in 21. Toxicity was moderate and reversible and consisted mainly of fever, flu-like symptoms, nausea, weight loss and hepatotoxicity. Anaemia, leucocytosis and thrombocytosis and induction of acute phase protein synthesis were noted in most patients. In 15% of the patients anti-IL-6 antibodies developed, and were neutralising in only one patient. Baseline plasma IL-6 concentrations did not correlate with tumour behaviour before or after rhIL-6 treatment. In conclusion, rhIL-6 can be safely administered on an outpatient basis for prolonged period of time and has moderate, reversible toxicity. Its administration induces IL-6-antibody production in only a minority of patients. Antitmour effects of rhIL-6 in metastatic renal cancer are limited.

Gemcitabine is a fluorine-substituted cytarabine analog with broad experimental antitumor activity. It's activity was explored in chemotherapy-naive patients with advanced progressive renal-cell carcinoma. A total of 39 patients were included in the study, of whom 37 were fully evaluable. In five patients the primary tumor remained in situ. Gemcitabine at 800 mg/m2 was given as a weekly 30-min infusion for 3 consecutive weeks followed by 1 week of rest. One complete response and two partial responses were observed giving a response rate of 8.1% [95% confidence interval (CI), 2-22%]. The duration of the responses is currently 32, 15, and 19 months, respectively. The median survival for all patients was 12.3 months. Gemacitabine was generally well tolerated, with nausea and vomiting (20.5% grade III) and neutropenia (5.3% grade III) being the most significant side effects. Gemcitabine given at this dose level and on this schedule has only limited activity in advanced renal-cell carcinoma.

In the treatment of renal cell carcinoma both complete (CRs) and partial remissions (PRs) have been obtained using recombinant (r) interferon alpha (IFN-alpha), with response rates ranging from 0 to 31% (mean 16%). rIFN-gamma is a potent immunostimulating agent, but the clinical experience of its use is limited and results are conflicting. In a phase II study with the combination of rIFN-alpha 2c (Boehringer Ingelheim) and rIFN-gamma (Genentech, supplied by Boehringer Ingelheim) in 31 eligible patients, a response rate of 25% was recorded. Based on this observation a randomised phase III study was initiated to investigate the possible advantage of the addition rIFN-gamma to rIFN-alpha 2c treatment. Treatment consisted of rIFN-alpha 2c 30 micrograms m-2 = 10 x 10(6) IU m-2 s.c. twice weekly in arm A and the same dose of rIFN-alpha combined with rIFN-gamma 100 micrograms m-2 = 2 x 10(6) IU m-2 in arm B. Eligibility criteria included documented progression of disease; patients with bone lesions only and overt central nervous system metastases were excluded. Between November 1988 and September 1990, 102 patients were entered into the study. An interim analysis showed a response in 7/53 (13%) patients (two CRs and five PRs) in the rIFN-alpha 2c monotherapy arm and in 2/45 (4%) (one CR and one PR) patients in the combination arm. This difference was not statistically significant (P = 0.17). The probability of missing an eventual 10% advantage for the combination is 0.001. The numbers are insufficient to rule out a negative effect of the addition of rIFN-gamma. The dose intensity of IFN-alpha 2c for the two treatment arms was the same. The addition of rIFN-gamma does not improve the response rate of rIFN-alpha 2c monotherapy. A possible detrimental effect cannot be excluded.

Docetaxel (Taxotere), an analogue of paclitaxel, was tested in a phase II study in advanced renal cell carcinoma. Consenting patients with measurable lesions, adequate organ functions and no prior chemotherapy received 100 mg/m2 of docetaxel as a 1-h infusion every 3 weeks. No premedication to avoid hypersensitivity reactions or nausea and emesis was given. 32 eligible patients received 100 treatment cycles. Short-lasting neutropenia was the dose-limiting toxicity. Acute hypersensitivity reactions (HSR), oedema and skin changes were other important side-effects. HSRs regressed spontaneously or were treated with antihistamines with or without corticosteroids. One partial remission was documented. At the dose and schedule used, docetaxel has only low activity against renal cell carcinoma.

In a patient with diffuse pulmonary metastases of a renal cell carcinoma the development of severe pulmonary hypertension is described after reaching a complete remission during treatment with r-IFN-alpha 2c and rIFN-gamma. Rechallenge with interferon after the discovery of recurrent disease did not lead to deterioration of the cardiopulmonary condition. Possible causative mechanisms are discussed.

Human leukocyte antigen (HLA) classes I and II molecules are essential for antigen presentation to cytotoxic T cells and helper T cells, respectively. Consequently, they may play a role in anticancer immunotherapy as well. We studied whether the pretreatment HLA phenotype of the tumor is predictive for response to interferon immunotherapy in vivo. Therefore, renal cell carcinoma (RCC) primary tumor lesions from 31 patients treated with interferon-alpha and interferon-gamma (13 responders and 18 nonresponders) were analyzed retrospectively for HLA antigen expression with immunohistochemical methods. Furthermore, from eight patients, pretreatment metastatic lesions were examined. In the primary tumors HLA class I expression was high: in 26 of 30 lesions more than 50% cells were stained. HLA class II expression was mostly low: in 14 of 31 primary tumors less than 5% cells were stained. A significant correlation was found between HLA phenotype of primary tumors and corresponding metastases. There was no association between tumor HLA classes I and II antigen expression and clinical response to interferon therapy. In conclusion, pretreatment HLA phenotype of RCC has no predictive value for outcome of interferon immunotherapy. A role for treatment-induced changes in HLA expression in vivo, however, can not be excluded. These findings do not provide indications for the working mechanism of interferon immunotherapy in vivo.

The efficacy of a low-dose regimen of human recombinant interferon-gamma was studied in 40 patients with metastatic or locally advanced renal cell carcinoma. Patients received 100 micrograms/m2/day as an infusion over 4 h. The intention was to find an active but tolerable regimen as a basis for future combination treatments with other cytokines or cytotoxic drugs. Activity of this low-dose schedule had been reported. In the absence of rapid progression, treatment was given for at least 3 months, and in case of stable disease it was continued for prolonged periods in order not to miss late remissions. Toxicity was generally mild, with fever and constitutional symptoms predominating. Therapeutic efficacy was low with only one partial remission. Three patients had stable disease over 6, 9, and 15 months. This low-dose schedule cannot be recommended for the treatment of renal cell cancer.

In vitro studies have documented the synergistic antiviral and antiproliferative activity of recombinant interferon alpha (rIFN alpha) and rIFN gamma. Furthermore, rIFN gamma is a strong immunomodulator with optimal effects at a relative low dose (0.1 mg/m2). On the basis of these observations, we began a phase I/II study with the combination of rIFN gamma at 100 micrograms/m2 (2 x 10(6) IU/m2) and rIFN alpha 2c 6 micrograms/m2 (2 x 10(6) IU/m2), injected twice a week subcutaneously. In cases of stable or progressive disease we increased the dose of rIFN alpha 2c every 2 weeks by 6 micrograms/m2 until the maximum tolerated dose was reached. A total of 32 patients with proven progressive renal-cell carcinoma were included. Of the 31 eligible patients, 21 were male and 10 female, their average age was 57.2 years (range 35-72), 28 had had nephrectomy, their median Karnofsky performance status was 90% (70%-100%), and their tumors were localized predominantly to visceral tissue. In 2, response was complete and in 6 it was partial, for a response rate of 25%. The disease had stabilized in 5 patients and progressed in 16. The median duration of partial response was 14 months (8-16 months); of 2 cases of complete response, 1 persists (23+ months), and the other suffered a relapse after 22 months. The median time to response was 24 weeks (18-24 weeks). The maximum tolerated dose of rIFN alpha was 30 micrograms/m2 (range of 6-36 micrograms/m2). Side-effects included those known to be associated with interferon treatment. One patient developed septicemia during a period with grade 4 leukopenia. Our study permits no conclusion regarding the additional value of rIFN gamma.

Thirty-two patients with proven progressive metastatic renal cell carcinoma were treated with the combination of 0.1 mg/m2 (2 X 10(6) IU/m2) r-interferon (r-IFN)-gamma and 6 micrograms/m2 (2 X 10(6) IU/m2) r-IFN-alpha. In case of progressive disease (PD) or stable disease (SD), after 8 weeks, the dose of r-IFN-alpha was escalated by 6 micrograms/m2 every 2 weeks until the maximum tolerable dose was reached, while r-IFN-gamma was maintained at the low dose. The rationale for this study is provided by the dose-related efficacy of IFN-alpha as a monotherapy, the potent immunostimulatory activity of IFN-gamma, and the alleged synergistic effect of the combination. Fourteen patients are evaluable for 8 weeks of low-dose combination treatment (7 X SD, 5 X PD, 2 X early progression), while so far 6 of 24 patients (25%) who started dose escalation of IFN-alpha have reached a partial response. These data indicate better efficacy with higher doses of IFN-alpha. Because of the infrequent administration and the relative low doses, compared to other trials, the treatment regimen was well tolerated. Although preliminary results are promising, definite efficacy remains to be proven.

A total of 66 patients with advanced renal cell cancer received a combination of recombinant interferon alpha-2a (18 times 10(6) units subcutaneously 3 times weekly) and vinblastine (0.1 mg. per kg. intravenously every 3 weeks). Four patients were ineligible and 6 were inevaluable for response but evaluable for toxicity. There were no complete and 9 partial responses among the 56 evaluable patients, for a response rate of 16 per cent. Median duration of response was 26 weeks, with a range of 8 to 50 weeks. Responses were observed predominantly in patients with lung and soft tissue metastases. Patients who had undergone nephrectomy did not show a better response rate than those who had not. Almost all patients had a flu-like syndrome, fatigue and anorexia. Other side effects included leukopenia, nausea, vomiting, liver function disturbances and neurotoxicity. Most of the side effects were World Health Organization grade 1 or 2; no grade 4 toxicity was observed. Antibodies against interferon developed in 6 patients during the course of treatment. However, there was no relationship between the appearance of antibodies and disease progression. The combination of recombinant interferon alpha-2a and vinblastine has modest but definite activity in patients with advanced renal cell carcinoma, although the role of vinblastine is unclear.