Possibilities for transborder cooperation in breast cancer care in Europe: a comparative analysis regarding the content, quality and evidence use of breast cancer guidelines.

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.

[Angiogenesis inhibitors for the systemic treatment of metastatic renal cell carcinoma: sunitinib, sorafenib, bevacizumab and temsirolimus]. / Angiogeneseremmers voor de systemische behandeling van gemetastaseerd niercelcarcinoom: sunitinib, sorafenib, bevacizumab en temsirolimus.

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'.

[Guideline 'Renal cell carcinoma']. / Richtlijn 'Niercelcarcinoom'.

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.

Dynamics in chimerism of T cells and dendritic cells in relapsed CML patients and the influence on the induction of alloreactivity following donor lymphocyte infusion.

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.

Intensive induction chemotherapy with C-BOP/BEP for intermediate- and poor-risk metastatic germ cell tumours (EORTC trial 30948).

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.

Timely withdrawal of G-CSF reduces the occurrence of thrombocytopenia during dose-dense chemotherapy.

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.

Leptomeningeal carcinomatosis in relapsed non-seminoma testis: a 1-year complete remission with high-dose chemotherapy.

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.

Novel treatment strategies in clear-cell metastatic renal cell carcinoma.

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.

Novel treatments for metastatic renal cell carcinoma.

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.

The quality of chemotherapy and its quality assurance.

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.

[A young man with rapidly progressing dyspnoea and a mediastinal mass]. / Een jonge man met snel progressieve dyspnoe en een mediastinale massa.

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.

European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG).

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.

Adherence to the guidelines of the CCCE in the treatment of node-positive breast cancer patients.

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.

[Surgical treatment of tumor metastases in the lungs, brain or liver]. / Chirurgische behandeling van tumormetastasen in longen, hersenen of lever.

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.

Effects of quality of treatment on prognosis in primary breast cancer patients treated in daily practice.

UNLABELLED: Information on treatment outcome outside clinical trials is sparse. This is the first study that relates surgical and medical quality of care in daily practice with outcome. BACKGROUND: In a previous study we showed, that the quality of chemotherapy as described by a guideline and given in daily practice to premenopausal primary breast cancer patients was suboptimal with only 68% and 53% of the patients receiving chemotherapy with a dose intensity (DI) and relative dose intensity (RDI) of > or = 85%, respectively. Many invalid reasons for delay and dose reductions were identified. PATIENTS AND METHODS: Premenopausal node-positive primary breast cancer patients treated from 1988 to 1992 were traced using two national registries. Relevant data were collected from their records. The following treatment-related variables were correlated with prognosis: type of surgery, number of investigated lymph nodes, radiotherapy, chemotherapy, interval between surgery and start of chemotherapy, DI, duration, delays and dose adjustments of chemotherapy and hospital size. RESULTS: Twenty-four of the 254 traced patients did not receive any chemotherapy, 230 received the recommended schedule of cyclophosphamide (C), methotrexate (M) and 5-fluorouracil (F). The median time of follow-up was 6.7 (range 0.9-10.2) years. The 5-year disease-free survival (DFS) and overall survival (OS) was 61% and 77%, respectively. In an univariate analysis DI < 65% correlated with a worse DFS and OS (p=0.05 and p=0.03, respectively). The use of chemotherapy correlated with a better DFS (p=0.03) than no use. In a multivariate analysis DI between 65 and 85% resulted in a better DFS (p=0.02) than DI > or = 85% and DI < 65%. CONCLUSION: The prognosis of the breast cancer patients in this population was comparable with the results of randomised trials using adjuvant CMF. The only treatment related variable of value for prognosis was DI. Unexpectedly DI between 65% and 85% resulted in the best prognosis in this population. The relevance of this observation remains unclear and warrants further investigation.

Prognostic and predictive factors of immunotherapy in metastatic renal cell carcinoma.

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.