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CD8(+) T cells recognizing minor histocompatibility antigens (MiHA) on solid tumor cells may mediate effective graft-versus-tumor (GVT) reactivity after allogeneic stem cell transplantation (SCT). Previously, we identified LRH-1 as a hematopoietic-restricted MiHA encoded by the P2X5 gene. Here, we report that LRH-1 is aberrantly expressed on solid tumor cells. P2X5 mRNA expression is demonstrated in a significant portion of solid tumor cell lines, including renal cell carcinoma (RCC), melanoma, colorectal carcinoma, brain cancer and breast cancer. Importantly, P2X5 gene expression was also detected in a subset of primary solid tumor specimens derived from RCC, brain cancer and breast cancer patients. Furthermore, P2X5 expressing solid tumor cells can be effectively targeted by LRH-1-specific cytotoxic T lymphocytes under inflammatory conditions. The expression of HLA-B7 and CD54 on tumor cells increases upon cytokine stimulation resulting in improved T cell activation as observed by higher levels of degranulation and enhanced tumor cell lysis. Overall, hematopoietic-restricted MiHA LRH-1 is aberrantly expressed on solid tumor cells and may be used as target in GVT-specific immunotherapy after SCT.

The objectives of this study were to investigate the effects of intratumorally (i.t.) administered recombinant human interleukin-12 (rhIL-12) on the distribution and function of B cells in the primary tumors, the locoregional lymph nodes and peripheral blood of head and neck squamous cell carcinoma (HNSCC) patients. The initial characterization of the patients participating in the phase Ib and phase II studies has previously been reported. After rhIL-12 treatment, fewer secondary follicles with a broader outer region of the mantle zones and an increase in interfollicular B-blasts were seen in the enlarged lymph nodes compared with control HNSCC patients. The size of the germinal center (GC) was diminished, partly due to a decrease in the number of CD57+ GC cells that have been associated with immune suppression. These changes did not correlate with signs of apoptosis or CXCR5 expression by B cells. Strikingly, in 3 out of 4 IL-12 treated patients, increased IFN-gamma mRNA expression by B cells was detected. In addition, a highly significant IgG subclass switch was seen in the plasma with more IgG1, less IgG2 and more IgG4, indicating a switch to T helper 1 phenotype. Finally, peritumoral B cell infiltration was a positive prognostic sign for overall survival in the 30 HNSCC patients investigated, irrespective of IL-12 treatment. In conclusion, these data indicate that after i.t. IL-12 treatment in HNSCC, significant activation of the B cell and the B cell compartment occurred and that the presence of tumor infiltrating B cells correlated with overall survival of HNSCC patients., ((c) 2008 Wiley-Liss, Inc.)

To encourage transborder cooperation in breast cancer care in Europe, we explored possibilities with the German-Dutch border area as an example. Evidence-based breast cancer guidelines were searched and compared on the: (1) methodological quality (with AGREE (Appraisal of Guidelines for Research and Evaluation)), (2) content of recommendations and (3) evidence use. The methodological quality of the German (n=2) and Dutch guidelines (n=2) was generally sufficient and comparable, although the applicability and the editorial independence were not clearly documented in the Dutch guidelines. Regarding the content analysis, German recommendations were taken as a reference point, because of the highest AGREE scores. Twenty-one of 25 recommendations discussed in both guidelines were corresponding and 4 were different, 32 were not mentioned in the Dutch guideline. The guidelines shared little evidence (< or =11%). We conclude that there are possibilities to encourage transborder cooperation. The clinical context of our results should be examined by measuring the actual care in both countries preferably with quality indicators.

Objectives: The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands., Methods: Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update., Results: The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma., Conclusions: Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

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.

Donor lymphocyte infusion (DLI) after allogeneic SCT induces complete remissions in approximately 80% of patients with relapsed CML in chronic phase, but some patients do not respond to DLI. We studied absolute numbers of dendritic cell (DC) subsets and chimerism in T cells and two subsets of blood DCs (myeloid DCs (MDCs) and plasmacytoid DCs (PDCs)) in relation to DLI-induced alloreactivity. Based on T cell and DC chimerism, we identified three groups. Four patients were completely donor chimeric in T cells and DC subsets. These patients had an early stage of relapse, and three of the four patients attained complete molecular remission (CMolR) without significant GVHD. Six patients were completely donor in T cells and mixed chimeric in DC subsets. All patients entered CMolR, but this was associated with GVHD in four and cytopenia in three patients. Five patients had mixed chimerism in T cells and complete recipient chimerism in MDC; only two patients entered CMolR. Our data suggest that the combination of donor T cells and mixed chimerism in DC subsets induces a potent graft-versus-leukemia (GVL) effect in association with GVHD. DLI in patients with an early relapse and donor chimerism in both T cells and DC subsets results in GVL reactivity without GVHD.

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.

New chemotherapy regimens are continuously explored in patients with high-risk malignant germ cell tumours (MGCTs). This multicentre phase II trial assessed the efficacy and toxicity of C-BOP/BEP chemotherapy in intermediate and poor prognosis MGCT (IGCCCG criteria). C-BOP/BEP treatment consisted of cycles of cisplatin, vincristine, bleomycin and carboplatin, followed by one cycle of vincristine and bleomycin and three cycles of BEP (bleomycon, etoposide, cisplatin). The trial was designed to demonstrate a 1-year progression-free survival rate of 80%, that is, to exclude a 1-year rate of 70% or less, with a one-sided significance level of 5%. Secondary end points included toxicity, overall survival and the postchemotherapy complete response rate. In total, 16 European hospitals entered 66 eligible patients (intermediate prognosis group: 37; poor prognosis group: 29). A total of 45 patients (68.2%, 95% confidence interval (95% CI): 56.9-79.4%) achieved a complete response (intermediate prognosis: 30; poor prognosis: 15). After a median observation time of 40.4 months (range: 13.7-66.3), the 1-year progression-free survival rate was 81.8% 95% CI: 72.5-91.1%). The 2-year overall survival was 84.5% (95% CI: 75.6-93.3%). In all, 51 patients experienced at least one episode of WHO grade 3/4 leucopenia, and at least one event of grade 3/4 thrombocytopenia occurred in 30 patients. There was no toxic death. With an 82% 1-year progression-free survival and a lower limit of the 95% CI above 70%, the efficacy of C-BOP/BEP is comparable to that of published alternative chemotherapy schedules in high-risk MGCT patients. The treatment's toxicity is manageable in a multicentre setting. In poor prognosis patients, C-BOP/BEP should be compared to standard chemotherapy of four cycles of BEP.

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.

Background: Post chemotherapy Granulocyte colony stimulating factor (G-CSF) reduces leucopenia, while G-CSF priming shortly before chemotherapy increases myelotoxicity. We performed a trial with a two-schedule crossover design to determine the optimal G-CSF schedule for densified 2-weekly chemotherapy., Methods: During 2-weekly chemotherapy days 1 and 2, G-CSF was given on days 3-10, with a G-CSF-free interval before the next chemotherapy cycle of 5 days, or on days 3-13, with a G-CSF-free interval of 2 days. In schedule A, cycle II was preceded by a 5 days, cycle III and IV by a 2 days and cycle V by a 5 days G-CSF free interval. In schedule B, this was 2, 5, 5, and 2 days, respectively., Results: Intra-patient comparison for cycles II versus III and cycles IV versus V showed that platelet (PLT) nadir count was significantly lower for cycles preceded by a 2-days compared to a 5-days G-CSF free interval: mean difference 45.7 x 10(9)/l (95% CI 33.2-58.2, p = 0.0001). Neutrophil count did not differ significantly (p = 0.85)., Conclusion: Timely withdrawal of G-CSF in dose-dense chemotherapy reduces chemotherapy-related thrombocytopenia. Leucopenia was not aggravated, reflecting a protective effect of post-chemotherapy G-CSF.

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.

A 1-year complete remission could be achieved with high-dose systemic chemotherapy in a 33-year-old patient with relapsed germ cell tumor presenting with leptomeningeal carcinomatosis (LC). Although LC in general has a very poor prognosis for patients with chemosensitive malignancies, systemic chemotherapy should be considered.

Aims: Assessment of the quality of chemotherapy care and its quality assurance in clinical trials and daily practice., Methods: Using Medline, literature was searched combining the following words: quality assurance or quality of care, combined with anti-neoplastic agents. The bibliography of each article was reviewed for additional literature. Those reports in English, French, German or Dutch focusing quality assurance or quality of care and chemotherapy were selected., Results: One hundred and five articles were selected by Medline and after review and adding of additional literature 53 articles remained. In clinical trials information on quality of chemotherapy is sparse. Different cooperative groups reported on suboptimal dosing, suboptimal registration of chemotherapy and several trials indicated that suboptimal dosing led to impaired outcome. Most quality assurance activities in clinical trials are concerned with audit and feedback and on-site visits. In daily practice the quality of chemotherapy is mostly impaired by the fact that it is not given although indicated and if it is given non-evidence based chemotherapy or administration schedules and reduced dose intensity decrease the quality of care. Especially, age, comorbidity and socio-economic status reduce the chance of receiving good quality of care regarding chemotherapy. Activities mostly used for quality assurance are generation of guidelines, specialisation and multidisciplinary care., Conclusions: Most quality assurance activities in clinical trials and daily practice are directed to structure and process parameters. More evidence that quality of care is related to outcome should be sought. Quality assurance in daily practice should aim at guideline implementation, specialisation and multidisciplinary care and should pay attention especially to the older patients, patients with comorbidity and patients from lower socio-economic classes.

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: Interleukin-12 is an anti-angiogenic and antitumor agent in many transplanted murine tumour models. In a previous clinical study in head and neck squamous cell carcinoma patients treated with rhIL-12 the tumour turned pale, after an initial reddening. The aim of this study was to investigate the effects of rmIL-12 on the vasculature, blood perfusion, hypoxia and proliferation of tumour cells in an implanted human head and neck squamous cell carcinoma xenograft tumour, with a relatively large diameter, in Balb/c nu/nu mice over time., Materials and Methods: Established human squamous cell carcinoma xenograft tumours were intratumorally injected for 3 days with either 200 ng rmIL-12 or PBA. Mice were sacrificed at 4 different time points (between 8 hours and 8 days after the last injection), after administration of Pimonidazole, BrdUrd and Hoechst 33342. The tumour sections were quantitatively analysed with a semi-automatic method based on a computerised digital image analysis system, after immunohistochemical staining., Results: Despite a faster and higher up-regulation of anti-mouse ICAM-1 in the IL-12-treated tumours, no significant differences in vascular density, perfusion fraction, hypoxic fraction and BrdUrd labelling index were detected between IL-12-treated tumour and control tumours., Conclusion: We suggest that the main reason why the observation made in humans could not be confirmed in this mice study is the combination of a lack of an intact immune system in the Balb/c nu/nu mice and a relatively large tumour with probably a lot of mature vessels.

The objective of this study was to evaluate the histologic and immunohistopathologic effects of intratumorally given recombinant human interleukin-12 on the immune cells in the primary tumors and regional lymph nodes. Ten previously untreated patients with head and neck squamous cell carcinoma (HNSCC) were injected in the primary tumor twice to thrice, once weekly, at two dose levels of 100 or 300 ng/kg, before surgery. These patients were compared with 20 non-IL-12-treated control HNSCC patients. In the primary tumor, the number of CD56+ natural killer (NK) cells was increased in IL-12-treated patients compared with control patients. In some IL-12-treated patients, an impressive peritumoral invasion of CD20+ B cells was noticed. No differences were seen in the CD8+ or CD4+ T lymphocytes. Interestingly, major differences were apparent in the architecture of the enlarged lymph nodes of IL-12-treated patients; in particular, the distribution of B cells differed and fewer primary and secondary follicles with smaller germinal centers were observed. In addition, a decrease of dendritic cell lysosyme-associated membrane glycoprotein-positive cells in the paracortex was noted, resulting in a reduction of paracortical hyperplasia. In the lymph nodes, especially the CD56+ NK cells but also the CD8+ and CD4+ T lymphocytes, produced a high amount of IFN-gamma. Patients, irrespectively of IL-12 treatment, with a high number of CD56+ cells in the primary tumor had a better overall survival than those with a low number. In conclusion, after i.t. IL-12 treatment in HNSCC patients, the largest effect was seen on the NK cells, with a higher number in the primary tumor and a high IFN-gamma mRNA expression in the lymph nodes. Significant effects were noted on B cells, with altered lymph node architecture in every IL-12-treated patient and excessive peritumoral infiltration in some patients.

An 18-year-old male presented with a 2-week history of rapid progressive dyspnoea and dry cough due to a large mediastinal mass with compression of the trachea. Based on the raised serum values of the tumour markers chorionogonadotrophin and alphafoetoprotein the diagnosis of germ-cell tumour was made. Because of the severity of his symptoms chemotherapy with bleomycin, etoposide and cisplatin was begun on the same day and before the results of the histology investigations were known. The next day the symptoms were diminished and after completing four courses of chemotherapy there was complete remission. The differential diagnosis of a rapid progressive mediastinal mass is limited and mainly relates to malignant lymphoma and germ-cell tumours. In emergency situations if tumour markers are raised then anti-tumour therapy may be begun before any histological confirmation is available.

Germ cell tumour is the most frequent malignant tumour type in young men with a 100% rise in the incidence every 20 years. Despite this, the high sensitivity of germ cell tumours to platinum-based chemotherapy, together with radiation and surgical measures, leads to the high cure rate of > or = 99% in early stages and 90%, 75-80% and 50% in advanced disease with 'good', 'intermediate' and 'poor' prognostic criteria (IGCCCG classification), respectively. The high cure rate in patients with limited metastatic disease allows the reduction of overall treatment load, and therefore less acute and long-term toxicity, e.g. organ sparing surgery for specific cases, reduced dose and treatment volume of irradiation or substitution of node dissection by surveillance or adjuvant chemotherapy according to the presence or absence of vascular invasion. Thus, different treatment options according to prognostic factors including histology, stage and patient factors and possibilities of the treating centre as well may be used to define the treatment strategy which is definitively chosen for an individual patient. However, this strategy of reduction of treatment load as well as the treatment itself require very high expertise of the treating physician with careful management and follow-up and thorough cooperation by the patient as well to maintain the high rate for cure. Treatment decisions must be based on the available evidence which has been the basis for this consensus guideline delivering a clear proposal for diagnostic and treatment measures in each stage of gonadal and extragonadal germ cell tumour and individual clinical situations. Since this guideline is based on the highest evidence level available today, a deviation from these proposals should be a rare and justified exception.

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.

The objective of this Phase II study was to evaluate the pharmacodynamic and immune effects of intratumorally administered recombinant human interleukin-12 (IL-12) on regional lymph nodes, primary tumor, and peripheral blood. Ten previously untreated patients with head and neck squamous cell carcinoma were injected in the primary tumor two to three times, once/week, at two dose levels of 100 or 300 ng/kg, before surgery. We compared these patients with 20 control (non-IL-12-treated) patients. Toxicity was high, with unexpected dose-limiting toxicities at the 300 ng/kg dose level. Dose-dependent plasma IFN-gamma and IL-10 increments were detected. These cytokine levels were higher after the first injection than after the subsequent injections. A rapid, transient reduction in lymphocytes, monocytes, and all lymphocyte subsets, especially natural killer cells, was observed, due to a redistribution to the lymph nodes. In the enlarged lymph nodes of the IL-12-treated patients, a higher percentage of natural killer cells and a lower percentage of T-helper cells were found compared with control patients. The same pattern was detected in the infiltrate in the primary tumor. Real-time semiquantitative PCR analysis of peripheral blood mononuclear cells in the peripheral blood showed a transient decrease of T-bet mRNA. Interestingly, the peripheral blood mononuclear cells in the lymph nodes showed a 128-fold (mean) increase of IFN-gamma mRNA. A switch from the Th2 to a Th1 profile in the lymph nodes compared with the peripheral blood occurred in the IL-12-treated patients. In conclusion, in previously untreated head and neck squamous cell carcinoma patients, recombinant human IL-12 intratumorally showed dose-limiting toxicities at the dose level of 300 ng/kg and resulted in measurable immunological responses locoregionally at both dose levels.

The Dutch Health Council has issued a report advising the government on the care of cancer patients and on palliative chemotherapy in particular. The term palliative chemotherapy is ambiguous and may lead to confusion because it does not mean intention of cure and because the Council makes the assumption that palliative chemotherapy is used to enhance the quality of life, which is not in fact the case. In daily oncological clinical practice, prolonging life is the main objective. The report should have focused on better objectives for the systemic treatment of cancer. Four recommendations are contained within the report: (a) participation in clinical trials should be encouraged; the current implementation of good clinical practice guidelines and the Medical Research (Human Subjects) Act do not provide much support for this recommendation; (b) medication for palliative chemotherapy should be assessed for cost effectiveness; this is a political assessment and the responsibility for its implementation should not lie with the medical profession; (c) the quality of palliative chemotherapy should be ensured, therefore its application should be restricted to the trained medical oncologists; (d) in view of the complexity of the treatment nationwide guidelines are needed.

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.

Guidelines are tools to improve the quality of care in daily practice. To accomplish adherence, active implementation is needed. The effect of audit, group-oriented feedback and educational activities to increase guideline adherence were investigated in this study. Treatment according to a guideline for premenopausal node-positive breast cancer patients from 1988 to 1992 (P1) and from 1996 to 1998 (P2) was assessed using the following indicators: percentage of patients with breast-conserving surgery, secondary surgery, > or = 10 reported resected axillary lymph nodes, reported tumour differentiation grade, reported hormonal receptor status, chemotherapy received (CT), start of CT < or = 28 days after surgery, Dose Intensity (DI) > or = 85% and completion of CT < or = 1 week beyond the ideal duration of CT. Data were audited from patients' records. The first audit resulted in a quality programme with feedback focused on the delivery of chemotherapy and resected axillary lymph nodes and educational sessions. A Fisher's exact test was used to estimate significant differences between the two time periods. In P1, 323 patients and in P2, 155 patients were eligible for treatment according to the guideline. The percentage of patients with > or = 10 lymph nodes improved from 65.3 to 81.3% (P=0.0004), as did the percentage with a reported oestrogen receptor (ER) status, from 84.8 to 96.8% (P=0.00004), progesterone receptor (PR) status from 82.3% to 97.4% (P<0.000001) and with a DI > or = 85%, from 74.9 to 93.9% (P=0.000003). Adherence varied between the hospitals. In conclusion, significant improvements were observed for the indicators of resected axillary lymph nodes and DI of chemotherapy, which may be attributed to the quality programme. Repeated assessment of the adherence to the guideline is important to observe changes and interhospital variations in order to remain focused on areas for improvement.

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.

The aim of this study was to evaluate the tolerability of intratumoral administered recombinant human interleukin-12 (rhIL-12) in patients with head and neck squamous cell carcinoma. Six patients were treated once a week at two dose levels of 100 or 300 ng/kg, respectively, up to 24 weeks. The primary end point was to assess the toxicity and safety of intratumoral injected rhIL-12 in head and neck squamous cell carcinoma patients; the pharmacokinetics and pharmacodynamics of rhIL-12 and any evidence of antitumor effect were also determined. Toxicity was mild, with prolonged grade 4 lymphopenia observed in only one patient. No dose-limiting toxicities occurred. In all six patients, the rhIL-12 was detectable in plasma within 30 min. Significant reductions in absolute number of peripheral blood lymphocytes and all lymphocyte subsets, especially cytotoxic T cells and natural killer cells, were observed that were maximal between 12 and 24 h. Maximal plasma concentrations of IFN-gamma and IL-10 were detected after 12 h. A real-time semiquantitative PCR analysis in peripheral blood mononuclear cells showed a mean increase of mRNA encoding IFN-gamma of 2.2 times relative to the pretreatment sample. An unexpected, significant decrease of 80% in T-bet mRNA, a T-helper 1 transcription factor, was detected after 12 h, with normalization after 48-72 h. No complete or partial responses were observed. In one patient, a 40% regression of a tumor lesion was noted. In conclusion, rhIL-12 at these dose levels and schedule was well tolerated and resulted in measurable immunological responses.

Metastases are generally an expression of widespread disease and therefore warrant systemic treatment. However, clinical observations have revealed that local surgical treatment might be beneficial in the case of organ-confined metastatic disease. Randomised studies have revealed that in the case of brain metastases, metastasectomy followed by radiotherapy, has a favourable outcome with respect to both the quality of life and overall survival. Retrospective non-randomised studies in selected patient groups show prolonged post-treatment survival in the case of both lung and liver metastasectomy. The most important prognostic factors for metastasectomy are: disease control elsewhere in the body, tumour species, the patient's general condition, and the possibility of a total resection of the metastasis. These factors form the basis of the separate decision-making process for each individual patient.

Purpose: To describe global quality of life (GLQL) in patients with metastatic testicular cancer (TC) treated with four different schedules of bleomycin, etoposide, and cisplatin (BEP) chemotherapy (four v three cycles given over 5 v 3 days)., Patients and Methods: Quality-of-life data were prospectively collected in 666 patients with metastatic TC entered into the European Organization for Research and Treatment of Cancer (EORTC) Trial 30941/United Kingdom Medical Research Council Trial TE20, using the EORTC Quality-of-Life Questionnaire C30 and a TC module. Data were analyzed by a mixed effects model and by evaluation of clinically relevant changes at 2 years., Results: The pattern of GLQL changes was similar in the four groups. Two years after chemotherapy, 36% of patients displayed improved GLQL as compared with baseline, whereas GLQL had deteriorated in 13%. At 3 months, patients receiving the 3-day regimen experienced increased gastrointestinal (GI) toxicity more than those receiving the 5-day regimen, with the difference reaching the level of clinical relevance (>or = 10-point change) if four cycles were given. The 3-day schedule increased the 2-year risk of tinnitus, with clinical relevance demonstrated after four cycles. Long-term peripheral neuropathy and Raynaud-like phenomena were not associated with the number of cycles or days per cycle. At 2 years, Raynaud-like phenomena, tinnitus, or reduced hearing were reported by 21% to 26% of the patients., Conclusion: Because of the excess of acute GI toxicity and the increased risk of tinnitus after the 3-day regimen, we recommend the 5-day regimen if four cycles of BEP are planned. If only three cycles are to be given, then the 3-day regimen is acceptable, even given the increased risk of nausea/vomiting at 3 months.

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.

Purpose: To assess the toxicity profile and dose-limiting toxicities (DLTs), to determine the maximum-tolerated dose, and to study the pharmacokinetics of ZD9331 when administered orally to patients with advanced solid tumors., Patients and Methods: Patients were treated with oral ZD9331 given once daily (od) or twice daily (bid) for 5, 7, or 10 days; cycles were repeated every 21 days at doses ranging from 2.5 to 40 mg. For pharmacokinetic analysis, plasma sampling was performed during the first course and assayed using a validated liquid chromatographic-tandem mass spectrometry assay. Plasma levels of 2'-deoxyuridine were measured as a surrogate marker for TS inhibition., Results: Forty-two patients received a total of 166 courses. The DLTs were myelosuppression and skin rash. Dose escalation of oral ZD9331 from 2.5 to 40 mg, as a single daily dose, resulted in a less than proportional increase in the plasma area under the concentration-time curve of ZD9331. The plasma drug exposure per cycle for the schedules 20 mg od for 5 days, 10 mg od for 10 days, and 10 mg bid for 5 days, all resulting in a total dose per cycle of 100 mg, were comparable. One partial response was noted in a patient with gastric cancer., Conclusion: DLTs in this phase I study of oral ZD9331 were myelosuppression and skin toxicity. The recommended dose for phase II studies of oral ZD9331 is 20 mg od for 5 consecutive days, every 3 weeks.

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.

The purpose of this article is to review the most significant results of the clinical studies conducted in the past two decades by the EORTC Head and Neck Cancer Group (HNCG). As for phase III trials, the HNCG investigated, besides the efficacy of chemopreventive drugs, the impact of cytostatic agents on various therapeutic targets, in combination or not with surgery and chemotherapy. These targets were: (a) chemo-prevention in curatively treated early stage disease; (b) organ preservation programmes in patients with operable tumour, comparing immediate surgery versus first-line chemotherapy; (c) postoperative management of locally advanced tumours, comparing radio-chemotherapy versus radiotherapy alone. Other phase II and phase III studies were also completed to investigate drug activity in advanced and/or recurrent head and neck squamous cell and adenoid cystic carcinomas. The present article will also analyse the strategies developed within the Group in the field of translational research.

Quality assurance (QA) lately arrived in the medical arena in comparison to other fields. EORTC focused initially its attention on the aspects related to clinical trial data handling. In the late 1980s, the EORTC appointed a Quality Control Committee (QCC) with the remit to expand the QA activities to the main disciplines involved in cancer treatment. From 1990 to 1996, two projects supported by the European Commission enabled the QCC to address, amongst others, specific questions related to medical oncology. Both projects focused on the practices of chemotherapy delivery and the quality of data reporting. Following these projects, the QCC developed standard guidelines to advise on chemotherapy delivery and also a systemic chemotherapy checklist to enable an easy collection of essential data onto the patient's files. More recently, the EORTC QA Committee proposed a minimal set of quality control procedures to be implemented by all EORTC groups.