D.J. van Spronsen

Functional MRI techniques demonstrate early vascular changes in renal cell cancer patients treated with sunitinib: a pilot study

Abstract Objective: To assess the early vascular effects of sunitinib in patients with renal cell carcinoma (RCC) with diffusion-weighted magnetic resonance imaging (DWI), dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and T2* perfusion MRI. Patients and methods: In 10 patients with abdominal RCC lesions, DWI, DCE-MRI and T2* perfusion MRI measurements at 3 Tesla were performed at baseline, 3 and 10 days after start of sunitinib. VEGF-A plasma levels were measured on days 0, 3 and 10. Results: DWI showed a significant increase in the apparent diffusion coefficient (×10−6 s/mm2) from baseline (mean 1158, range 814–2003) to day 3 (mean 1306, range 1008–2097, P = 0.015) followed by a decrease to baseline levels at day 10 (mean 1132, range 719–2005, P = 0.001). No significant changes were found in mean DCE-MRI parameters. T2* perfusion MRI showed a significant decrease in relative tumor blood volume (rBV) and relative tumor blood flow (rBF) at day 3 (rBV P = 0.037, rBF P = 0.018) and day 10 (rBV P = 0.006, rBF P = 0.009). VEGF-A plasma levels significantly increased after 10 days, but did not correlate with MRI parameters. Conclusions: Sunitinib induces antiangiogenic effects as measured by DWI and T2*-perfusion MRI, 3 and 10 days after the start of the initial treatment. DCE-MRI did not show significant changes. In the near future, early functional MRI-based evaluation can play an important role in tailoring treatment to the individual patient with RCC. Further investigation is warranted.

Two sides of the medallion: poor treatment tolerance but better survival by standard chemotherapy in elderly patients with advanced-stage diffuse large B-cell lymphoma

BACKGROUND We investigated treatment of unselected elderly patients with diffuse large B-cell lymphoma (DLBCL) and its subsequent impact on treatment tolerance and survival. PATIENTS AND METHODS Data from all 419 advanced-stage DLBCL patients, aged 75 or older and newly diagnosed between 1997 and 2004, were included from five regional population-based cancer registries in The Netherlands. Subsequent data on comorbidity, performance status, treatment, motives for adaptations or refraining from chemotherapy and toxic effects was collected from the medical records. Follow-up was completed until 1st January 2009. RESULTS Only 46% of patients received the standard therapy [aggressive chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-like chemotherapy]. Motives for withholding chemotherapy were refusal by patient/family, poor performance status or estimated short life expectancy. Of all patients receiving CHOP-like chemotherapy, only 56% could complete at least six cycles. Grade 3 or 4 toxicity occurred in 67% of patients receiving standard therapy. The independent effect of therapy on survival remained after correction for the age-adjusted International Prognostic Index. CONCLUSIONS Standard therapy was applied less often in elderly patients with a subsequent independent negative impact on survival. Furthermore, high toxicity rate and the impossibility of the majority of patients to complete treatment were seen. This implies that better treatment strategies should be devised including a proper selection of senior patients for this aggressive chemotherapy.BACKGROUND We investigated treatment of unselected elderly patients with diffuse large B-cell lymphoma (DLBCL) and its subsequent impact on treatment tolerance and survival. PATIENTS AND METHODS Data from all 419 advanced-stage DLBCL patients, aged 75 or older and newly diagnosed between 1997 and 2004, were included from five regional population-based cancer registries in The Netherlands. Subsequent data on comorbidity, performance status, treatment, motives for adaptations or refraining from chemotherapy and toxic effects was collected from the medical records. Follow-up was completed until 1st January 2009. RESULTS Only 46% of patients received the standard therapy [aggressive chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-like chemotherapy]. Motives for withholding chemotherapy were refusal by patient/family, poor performance status or estimated short life expectancy. Of all patients receiving CHOP-like chemotherapy, only 56% could complete at least six cycles. Grade 3 or 4 toxicity occurred in 67% of patients receiving standard therapy. The independent effect of therapy on survival remained after correction for the age-adjusted International Prognostic Index. CONCLUSIONS Standard therapy was applied less often in elderly patients with a subsequent independent negative impact on survival. Furthermore, high toxicity rate and the impossibility of the majority of patients to complete treatment were seen. This implies that better treatment strategies should be devised including a proper selection of senior patients for this aggressive chemotherapy.

Better survival in patients with metastasised kidney cancer after nephrectomy: a population-based study in the Netherlands.

AIM Cytoreductive nephrectomy is considered beneficial in patients with metastasised kidney cancer but only a minority of these patients undergo cytoreductive surgery. Factors associated with nephrectomy and the independent effect of nephrectomy on survival were evaluated in this study. METHODS Patients were selected from the population-based cancer registry and detailed data were retrieved from clinical files. Factors associated with nephrectomy were evaluated by logistic regression analyses. Cox proportional hazard regression analysis was performed to evaluate factors associated with survival; a propensity score reflecting the probability of being treated surgically was included in order to adjust for confounding by indication. RESULTS 37.5% of 328 patients diagnosed with metastatic kidney cancer between 1999 and 2005 underwent nephrectomy. Patients with a low performance score, high age, ≥2 comorbid conditions, ≥2 metastases, low or high BMI, weight loss, elevated lactate dehydrogenase, elevated alkaline phosphatase, female gender and liver or bone metastases were less likely to be treated surgically. Three year survival was 25% and 4% for patients with and without nephrectomy, respectively (p<0.001). After adjustment for other prognostic factors including the propensity score, nephrectomy remained significantly associated with better survival (Hazard ratio: 0.52, 95% Confidence interval: 0.37-0.73). CONCLUSIONS Even after accounting for prognostic profile, patients still benefit from a nephrectomy; an approximately 50% reduction in mortality was observed. It is, therefore, recommended that patients with metastasised disease receive cytoreductive surgery when there is no contraindication. Trial results on cytoreductive surgery combined with targeted molecular therapeutics are awaited for.

Conditional survival for long-term colorectal cancer survivors in the Netherlands: who do best?

AIM With the increase in the number of long-term colorectal cancer (CRC) survivors, there is a growing need for subgroup-specific analysis of conditional survival. METHODS All 137,030 stage I-III CRC patients diagnosed in the Netherlands between 1989 and 2008 aged 15-89 years were selected from the Netherlands Cancer Registry. We determined conditional 5-year relative survival rates, according to age, subsite and tumour stage for each additional year survived up to 15 years after diagnosis as well as trends in absolute risks for and distribution of causes of death during follow-up. RESULTS Minimal excess mortality (conditional 5-year relative survival >95%) was observed 1 year after diagnosis for stage I colon cancer patients, while for rectal cancer patients this was seen after 6 years. For stage II and III CRC, minimal excess mortality was seen 7 years after diagnosis for colon cancer, while for rectal cancer this was 12years. The differences in conditional 5-year relative survival between colon and rectal cancer diminished over time for all patients, except for stage III patients aged 60-89 years. The absolute risk to die from CRC diminished sharply over time and was below 5% after 5 years. The proportion of patients dying from CRC decreased over time after diagnosis while the proportions of patients dying from other cancers, cardiovascular disease and other causes increased. CONCLUSION Prognosis for CRC survivors improved with each additional year survived, with the largest improvements in the first years after diagnosis. Quantitative insight into conditional relative survival estimates is useful for caregivers to inform and counsel patients with stage I-III colon and rectal cancer during follow-up.

Treatment and complications in elderly stage III colon cancer patients in the Netherlands

BACKGROUND We evaluated which patient factors were associated with treatment tolerance and outcome in elderly colon cancer patients. DESIGN Population-based data from five regions included in the Netherlands Cancer Registry were used. Patients with resected stage III colon cancer aged ≥75 years diagnosed in 1997-2004 who received adjuvant chemotherapy (N = 216) were included as well as a random sample (N = 341) of patients who only underwent surgery. RESULTS The most common motives for withholding adjuvant chemotherapy were a combination of high age, co-morbidity and poor performance status (PS, 43%) or refusal by the patient or family (17%). In 57% of patients receiving chemotherapy, adaptations were made in treatment regimens. Patients who received adjuvant chemotherapy developed more complications (52%) than those with surgery alone (41%). For the selection of patients who had survived the first year after surgery, receiving adjuvant chemotherapy resulted in better 5-year overall survival (52% versus 34%), even after adjustment for differences in age, co-morbidity and PS. CONCLUSION Despite high toxicity rates and adjustments in treatment regimens, elderly patients who received chemotherapy seemed to have a better survival. Prospective studies are needed for evaluating which patient characteristics predict the risks and benefits of adjuvant chemotherapy in elderly colon cancer patients.

Validation, revision and extension of the Follicular Lymphoma International Prognostic Index (FLIPI) in a population-based setting

BACKGROUND The aim of this study was to validate the Follicular Lymphoma International Prognostic Index (FLIPI) in a population-based cohort and to study the relevance of revision and extension of the FLIPI. PATIENTS AND METHODS Data of 353 unselected patients, 1993-2002, in the Eindhoven Cancer Registry, were collected. Follow-up was completed up to 1 January 2006. Multiple imputations for missing covariates were used. Validity was assessed by comparing observed to predicted survival of the original model and of a revised model with other prognostic variables. RESULTS The original FLIPI stratified our cohort into three different risk groups based on stage, Hb, lactate dehydrogenase, nodal involvement and age. The discrimination between risk groups was not as good as in the original cohort. A model including age in three categories (< or =60/61-70/>70 years) and presence of cardiovascular disease (CVD) (yes/no) resulted in a better prognostic index. The 5-year overall survival rates were 79%, 59% and 28% in the low-, intermediate- and high-risk groups for the extended FLIPI compared with 81%, 66% and 47% for the original FLIPI, respectively. CONCLUSIONS The performance of the FLIPI was validated in a population-based setting, but could significantly be improved by a more refined coding of age and by including the presence of CVD.

Improved survival of Hodgkin's patients in South-East Netherlands since 1972

In the past 30 years, staging and treatment of Hodgkins disease have changed dramatically, and prolonged remission can now be induced in the majority of patients. Our purpose was to assess improvement in long-term survival, previously reported for specific patient groups, among unselected patients diagnosed and treated between 1972 and 1993 in general hospitals in South-East Netherlands. Data on all 345 Hodgkins patients were derived from the population-based Eindhoven Cancer Registry; histopathology and clinical records were reviewed. Follow-up was attained up to 1994. Relative survival rates, i.e. the ratio of observed to expected rates, were 80% after 5, 70% after 10 and 67% after 15 years. Independent prognostic factors for lower overall survival were (in decreasing order of significance): advanced age, histology (lymphocyte depletion), advanced stage and earlier period of diagnosis. Distribution of age and stage did not change over the study period, but there was a modest increase in the incidence of the nodular sclerosis histological subtype. Crude 5-year survival rates improved from 60% in the period 1972-1976 to 81% in the period of 1987-1992 (P < 0.005). The largest improvement occurred in the 1970s and was most prominent among those aged over 50 years. As previously reported, cured Hodgkins patients exhibit a higher mortality rate, which can be explained by treatment-related long-term complications such as second malignancies and cardiovascular diseases. The relatively high survival rates compared to other population-based studies may be attributable to the existence of a regional network within the framework of a comprehensive cancer centre. Better staging, new combinations of chemotherapy, improved radiation technology, advances in supportive care as well as more frequent intensive treatment of the elderly could explain the improvement in prognosis.

Doxorubicin/cyclophosphamide with concurrent versus sequential docetaxel as neoadjuvant treatment in patients with breast cancer

BACKGROUND This study was designed to determine whether delivering neo-adjuvant chemotherapy at a higher dose in a shorter period of time improves outcome of breast cancer patients. PATIENTS AND METHODS Women with newly diagnosed breast cancer were randomly assigned to neoadjuvant chemotherapy of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC 60/600 - T 100 mg/m(2)) or six cycles of TAC (75/50/500 mg/m(2)) every 3 weeks. The primary endpoint was the pathologic complete response (pCR) rate, defined as no invasive tumour present in the breast. RESULTS In total, 201 patients were included. Baseline characteristics were well balanced. AC-T resulted in pCR in 21% and TAC in 16% of patients (odds ratio 1.44 (95% confidence interval (CI) 0.67-3.10). AC-T without primary granulocyte-colony stimulating factor (G-CSF) prophylaxis was associated with more febrile neutropenia compared to TAC with primary G-CSF prophylaxis (23% versus 9%), and with more grade 3/4 sensory neuropathy (5% versus 0%). CONCLUSIONS With a higher cumulative dose for the concurrent arm, no differences were observed between the two treatment arms with respect to pCR rate. The differential toxicity profile could partly be explained by different use of primary G-CSF prophylaxis.

Small but significant excess mortality compared with the general population for long-term survivors of breast cancer in the Netherlands

BACKGROUND Coinciding with the relatively good and improving prognosis for patients with stage I-III breast cancer, late recurrences, new primary tumours and late side-effects of treatment may occur. We gained insight into prognosis for long-term breast cancer survivors. PATIENTS AND METHODS Data on all 205 827 females aged 15-89 diagnosed with stage I-III breast cancer during 1989-2008 were derived from the Netherlands Cancer Registry. Conditional 5-year relative survival was calculated for every subsequent year from diagnosis up to 15 years. RESULTS For stage I, conditional 5-year relative survival remained ~95% up to 15 years after diagnosis (a stable 5-year excess mortality rate of 5%). For stage II, excess mortality remained 10% for those aged 15-44 or 45-59 and 15% for those aged 60-74. For stage III, excess mortality decreased from 35% at diagnosis to 10% at 15 years for those aged 15-44 or 45-59, and from ~40% to 30% for those aged ≥60. CONCLUSIONS Patients with stage I or II breast cancer had a (very) good long-term prognosis, albeit exhibiting a small but significant excess mortality at least up to 15 years after diagnosis. Improvements albeit from a lower level were mainly seen for patients who had been diagnosed with stage III disease. Caregivers can use this information to better inform (especially disease-free) cancer survivors about their actual prognosis.

Need for early recognition and therapeutic guidelines of congenital sideroblastic anaemia

We present a patient with iron overload, who was initially diagnosed with hereditary haemochromatosis. Family analysis, however, established that the iron overload was secondary to congenital sideroblastic anaemia. The patient died of a hepatocellular carcinoma, likely a complication of iron overload, despite phlebotomies. Increased awareness, as well as development of evidence-based clinical guidelines, is required for timely diagnosis and adequate treatment.