Translating the ABC-02 trial into daily practice: outcome of palliative treatment in patients with unresectable biliary tract cancer treated with gemcitabine and cisplatin.

BACKGROUND: Biliary tract cancer (BTC) is an uncommon cancer with an unfavorable prognosis. Since 2010, the standard of care for patients with unresectable BTC is palliative treatment with gemcitabine plus cisplatin, based on the landmark phase III ABC-02 trial. This current study aims to evaluate the efficacy and safety of gemcitabine and cisplatin in patients with unresectable cholangiocarcinoma and gallbladder cancer in daily practice that meet the criteria for the ABC-02 trial in comparison to patients who did not. METHODS: Patients diagnosed with unresectable BTC between 2010 and 2015 with an indication for gemcitabine and cisplatin were included. We divided these patients into three groups: (I) patients who received chemotherapy and met the criteria of the ABC-02 trial, (II) patients who received chemotherapy and did not meet these criteria and (III) patients who had an indication for chemotherapy, but received best supportive care without chemotherapy. Primary outcome was overall survival (OS) and secondary outcome was progression-free survival (PFS). RESULTS: We collected data of 208 patients, of which 138 (66.3%) patients received first line chemotherapy with gemcitabine and cisplatin. Median OS of 69 patients in group I, 63 patients in group II and 65 patients in group III was 9.6 months (95%CI = 6.7-12.5), 9.5 months (95%CI = 7.7-11.3) and 7.6 months (95%CI = 5.0-10.2), respectively. Median PFS was 6.0 months (95%CI = 4.4-7.6) in group I and 5.1 months (95%CI = 3.7-6.5) in group II. Toxicity and number of dose reductions (p = .974) were comparable between the two chemotherapy groups. CONCLUSION: First-line gemcitabine and cisplatin is an effective and safe treatment for patients with unresectable BTC who do not meet the eligibility criteria for the ABC-02 trial. Median OS, PFS and treatment side effects were comparable between the patients who received chemotherapy (group I vs. group II).

Improved survival for sequentially as opposed to concurrently delivered neoadjuvant chemotherapy in non-metastatic breast cancer.

PURPOSE: The INTENS study was designed to determine whether delivering neoadjuvant chemotherapy at a higher dose in a shorter period of time improves outcome of breast cancer patients. METHODS: Women with newly diagnosed breast cancer were randomly assigned to neoadjuvant chemotherapy consisting of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC 60/600-T 100 mg/m2) or six cycles of TAC as triplet chemotherapy (75/50/500 mg/m2) every 3 weeks. The primary outcome was the pathologic complete response (pCR), with disease-free and overall survival as secondary endpoints. RESULTS: In total, 201 patients were included. The pCR rates were 28% for patients treated with AC-T and 19% for patients treated with TAC, with an odds ratio of 1.60 (95% CI 0.90-3.21). With a median follow-up of 6 years (range 0.04-8.41 years), the five-year disease-free survival was 81% for patients treated with sequentially AC-T and 71% for patients treated with concurrent triplet TAC chemotherapy with a stratified hazard ratio (HR) of 0.50 (95% CI 0.29-0.86). Five-year overall survival was 84% versus 76%, respectively, with a stratified HR of 0.55 (95% CI 0.29-1.03). CONCLUSIONS: No differences were observed between the two treatment arms with respect to pCR rate, but the sequentially delivered chemotherapy outperformed the triplet combination chemotherapy in terms of survival, despite a lower cumulative dose per agent. GOV nr NCT00314977.

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.

Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma.

BACKGROUND: The introduction of rituximab significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), emphasizing the importance of evaluating the long-term consequences of exposure to radiotherapy, alkylating agents and anthracycline-containing (immuno)chemotherapy among DLBCL survivors. METHODS: Long-term risk of subsequent malignant neoplasms (SMNs) was examined in a multicenter cohort comprising 2373 5-year DLBCL survivors treated at ages 15-61 years in 1989-2012. Observed SMN numbers were compared with expected cancer incidence to estimate standardized incidence ratios (SIRs) and absolute excess risks (AERs/10 000 person-years). Treatment-specific risks were assessed using multivariable Cox regression. RESULTS: After a median follow-up of 13.8 years, 321 survivors developed one or more SMNs (SIR 1.5, 95% CI 1.3-1.8, AER 51.8). SIRs remained increased for at least 20 years after first-line treatment (SIR ≥20-year follow-up 1.5, 95% CI 1.0-2.2, AER 81.8) and were highest among patients ≤40 years at first DLBCL treatment (SIR 2.7, 95% CI 2.0-3.5). Lung (SIR 2.0, 95% CI 1.5-2.7, AER 13.4) and gastrointestinal cancers (SIR 1.5, 95% CI 1.2-2.0, AER 11.8) accounted for the largest excess risks. Treatment with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin versus ≤2250 mg/m2/≤150 mg/m2, respectively, was associated with increased solid SMN risk (hazard ratio 1.5, 95% CI 1.0-2.2). Survivors who received rituximab had a lower risk of subdiaphragmatic solid SMNs (hazard ratio 0.5, 95% CI 0.3-1.0) compared with survivors who did not receive rituximab. CONCLUSION: Five-year DLBCL survivors have an increased risk of SMNs. Risks were higher for survivors ≤40 years at first treatment and survivors treated with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin, and may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up for rituximab-treated patients.

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.

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.

A pilot study on the immunogenicity of dendritic cell vaccination during adjuvant oxaliplatin/capecitabine chemotherapy in colon cancer patients.

BACKGROUND: Dendritic cell (DC) vaccination has been shown to induce anti-tumour immune responses in cancer patients, but so far its clinical efficacy is limited. Recent evidence supports an immunogenic effect of cytotoxic chemotherapy. Pre-clinical data indicate that the combination of chemotherapy and immunotherapy may result in an enhanced anti-cancer activity. Most studies have focused on the immunogenic aspect of chemotherapy-induced cell death, but only few studies have investigated the effect of chemotherapeutic agents on the effector lymphocytes of the immune system. METHODS: Here we investigated the effect of treatment with oxaliplatin and capecitabine on non-specific and specific DC vaccine-induced adaptive immune responses. Stage III colon cancer patients receiving standard adjuvant oxaliplatin/capecitabine chemotherapy were vaccinated at the same time with keyhole limpet haemocyanin (KLH) and carcinoembryonic antigen (CEA)-peptide pulsed DCs. RESULTS: In 4 out of 7 patients, functional CEA-specific T-cell responses were found at delayed type hypersensitivity (DTH) skin testing. In addition, we observed an enhanced non-specific T-cell reactivity upon oxaliplatin administration. KLH-specific T-cell responses remained unaffected by the chemotherapy, whereas B-cell responses were diminished. CONCLUSION: The results strongly support further testing of the combined use of specific anti-tumour vaccination with oxaliplatin-based chemotherapy.

Internal jugular vein thrombosis as paraneoplastic syndrome of primary ovarian non-Hodgkin's lymphoma.

Primary malignant lymphoma involving the ovaries is extremely rare. We present a unique case of a primary Non-Hodgkin's lymphoma (NHL) of both ovaries, preceded by an internal jugular vein trombosis (IJVT) as paraneoplastic syndrome. Currently, 36 months after surgical treatment of this FIGO Stage Ib, Ann Arbor Stage 2E NHL, the patient is clinically free of disease. Based on this case and a review of the literature it is concluded that paraneoplastic syndromes like spontaneous IJVT should prompt the clinician to make a thorough diagnostic work-up in search of an underlying malignancy, including the female genital tract.

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.

[Cardiotoxicity of trastuzumab of significance in the adjuvant treatment of breast cancer]. / Cardiotoxiciteit van trastuzumab van betekenis bij de adjuvante behandeling van borstkanker.

Three women aged 53, 52 and 36 years, respectively, underwent surgery for breast cancer, i.e. right-sided grade II invasive ductal carcinoma, left-sided grade III invasive ductal carcinoma, and left-sided multifocal grade III invasive ductal carcinoma, respectively. All 3 received adjuvant anthracycline-containing chemotherapy followed by trastuzumab. They developed significant cardiac dysfunction, as determined by a decrease in left ventricular ejection fraction (LVEF), which necessitated trastuzumab discontinuation. Trastuzumab therapy was resumed in the third patient after LVEF recovery but was stopped definitively when the LVEF decreased again. Trastuzumab has been shown to improve both disease-free and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, symptomatic cardiac failure due to cardiomyopathy has been observed in 0.6-4.1% of patients treated with trastuzumab after adjuvant anthracycline-based chemotherapy, whereas in 5-19% of the patients the decline in cardiac function led to permanent discontinuation of trastuzumab therapy. Cardiac function should be monitored regularly during trastuzumab therapy. An LVEF less than 50% or an absolute reduction of more than 10% warrant treatment discontinuation and close follow-up. Cardiac dysfunction is usually reversible; however, the long-term consequences of LVEF reduction following trastuzumab therapy are still unknown and warrant close attention, given the relatively young age and long life expectancy of these patients.

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.

Independent prognostic effect of co-morbidity in lymphoma patients: results of the population-based Eindhoven Cancer Registry.

The prevalence of co-morbidity among elderly lymphoma patients is associated with a decrease in the use of chemotherapy. This study assessed the independent prognostic effect of co-morbidity in 1551 unselected lymphoma patients, diagnosed between 1995 and 2001 in the area of the population-based Eindhoven Cancer Registry. The prevalence of serious co-morbidity was 58% for patients with Hodgkin's disease (HD) who were over 60 years of age and 66% for patients with non-Hodgkin's lymphoma (NHL) who were over 60 years of age. The administration of chemotherapy declined in the presence of co-morbidity for elderly patients with early-stage HD and elderly patients with aggressive NHL. Co-morbidity was associated with a 10-20% decline in 5-year survival. Whether less frequent application of chemotherapy in the presence of co-morbidity is justified as far as complications, prognosis and quality of life are concerned requires further investigation.

The standardised mortality ratio: the proper quality indicator in acute leukaemia?

BACKGROUND: The standardised mortality ratio (SMR) is a quality indicator used to measure quality of care in the Netherlands. It is subject to much criticism, which was the reason to study the value of the SMR as a quality indicator for the treatment of acute leukaemia. METHODS: A retrospective analysis was performed in patients with acute leukaemia admitted to a Santeon hospital during the period 2005-2009. SMR values were calculated and compared with the overall survival (OS). RESULTS: During the study period, 455 unique patients were admitted with acute leukaemia. SMR calculation was based on 992 admissions. SMR analysis yielded a high mortality ratio in hospital 1, 2, 3 and 4 in comparison with the national average (100), significant for hospital 1 and 4 (180 [CI 95% 126-257] and 187 [CI 95% 134-261], respectively) OS analysis also showed a significantly different outcome between hospitals. However, using OS as outcome parameter, hospital 2 and 6 showed the lowest performance as compared with hospital 1 and 4 using SMR as parameter. After multivariate analysis, age (HR 1.04; CI 95% 1.03-1.05; p < 0.001) and hospital (hospital 5 compared with 6: HR 0.54; CI 95% 0.30- .98; p = 0.043; hospital 2 compared with 1: HR 1.51; CI 95% 1.02-2.23; p = 0.039) were the only significant variables that influenced OS. CONCLUSION: Outcome according to SMR is not equivalent to outcome according to OS. This study shows that the use of the SMR as a quality indicator for the treatment of acute leukaemia does not appear to be justified.

Improved survival of Hodgkin's patients in south-east Netherlands since 1972.

In the past 30 years, staging and treatment of Hodgkin's 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 Hodgkin's 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 Hodgkin's 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.

New developments in staging and follow-up of patients with Hodgkin's lymphoma.

Adequate staging of newly diagnosed patients with Hodgkin's lymphoma enables optimal treatment planning, which is of particular importance for finding a balance between treatment efficacy and toxicity. In this review an overview is given of the current knowledge on initial staging and the role of imaging modalities during and after treatment. A promising new tool is whole-body positron emission tomograpy (PET) scanning with fluorodeoxyglucose (FDG). This modality is particularly useful for the evaluation of a residual mass at the end of treatment and for the assessment of the prognostically relevant 'early response' to chemotherapy. Although high survival rates have been reported for patients treated within the context of clinical trials these rates are generally lower in population-based series. In the general population comorbidity is present in half of all elderly Hodgkin patients. Since comorbidity has great impact on treatment planning and survival, this prognostic factor should be taken into account in future trials.

Common variable immunodeficiency in a family.

Common variable immunodeficiency (CVID) is mainly characterised by hypo- or agammaglobulinaemia of late onset, usually discovered in the second decade of life. In individuals CVID is associated with a variable impairment of cellular immunity and the susceptibility to microbial infection may vary as well. CVID is described in a mother and a son who suffered from serious bacterial infections. In addition, minor immunological test abnormalities of apparently healthy first degree relatives are described.

Acquired angio-oedema caused by IgA paraprotein.

The syndrome of acquired angio-oedema is characterized by late onset of recurrent bouts of angio-oedema or abdominal pain and may be caused by an acquired deficiency of C1-inhibitor (C1-INH), the inhibitor of the first component of complement. Acquired C1-INH deficiency has been described in approximately 50 patients and is strongly associated with malignant B-cell proliferations. We describe a patient with an 8-year history of recurrent abdominal symptoms and angio-oedema with acquired C1-INH deficiency, caused by the presence of IgA-kappa antibodies that inactivate C1-INH. Analysis of the bone marrow revealed an IgA-kappa monoclonal population of plasma cells, without evidence of overt myeloma. Angio-oedema caused by an autoantibody of the IgA isotype is extremely rare and has never been described in a Dutch patient. Recognition of angio-oedema, both hereditary and acquired, is important because of the therapeutic consequences, as will be discussed.

[Diagnostic image (92). A man with fever during chemotherapy. Invasive pulmonary mycosis]. / Diagnose in beeld (92). Een man met koorts tijdens chemotherapie. Invasieve pulmonale mycose.

A 64-year-old male was treated for acute myeloid leukemia with idarubicin and cytarabin. He developed pulmonary mycosis (radiologically consistent with aspergillosis), which responded to intravenous amphotericin B.

[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.

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.