The effects of new life-prolonging drugs for metastatic castration-resistant prostate cancer (mCRPC) patients in a real-world population.

BACKGROUND: In 2004 docetaxel was the first life-prolonging drug (LPD) registered for metastatic castration-resistant prostate cancer (mCRPC) patients. Between 2011 and 2014 new LPDs for mCRPC (cabazitaxel, abiraterone, enzalutamide, and radium-223) were introduced in the Netherlands. The objective of this study is to assess the impact of the introduction of new LPDs on treatment patterns and overall survival (OS) over time. PATIENTS AND METHODS: CRPC patients diagnosed in the years 2010-2016 in the observational, retrospective CAPRI registry (20 hospitals) were included and followed up to 2018. Two subgroups were analyzed: treatment-naïve patients (subgroup 1, n = 3600) and post-docetaxel patients (subgroup 2, n = 1355). RESULTS: In both subgroups, the use of any LPD increased: from 57% (2010-2011) to 69% (2014-2015) in subgroup 1 and from 65% (2011-2012) to 79% (2015-2016) in subgroup 2. Chemotherapy as first mCRPC-treatment (i.e., docetaxel) and first post-docetaxel treatment (i.e., cabazitaxel or docetaxel rechallenge) decreased (46-29% and 20-9% in subgroup 1 and 2, respectively), while the use of androgen-receptor targeting treatments (ART) increased from 11% to 39% and 46% to 64% in subgroup 1 and 2, respectively. In subgroup 1, median OS (mOS) from diagnosis CRPC increased from 28.5 months to 31.0 months (p = 0.196). In subgroup 2, mOS from progression on docetaxel increased from 7.9 months to 12.5 months (p < 0.001). After multiple imputations of missing values, in multivariable cox-regression analysis with known prognostic parameters, the treatment period was independent significant for OS in subgroup 1 (2014-2015 vs. 2010-2011 with HR 0.749, p < 0.001) and subgroup 2 (2015-2016 vs. 2011-2012 with HR 0.811, p = 0.037). CONCLUSION: Since 2010, a larger proportion of mCRPC patients was treated with LPDs, which was related to an increased mOS.

Randomised phase II/III study of docetaxel with or without risedronate in patients with metastatic Castration Resistant Prostate Cancer (CRPC), the Netherlands Prostate Study (NePro).

BACKGROUND: This multicentre, randomised, open label, phase II/III study aimed to investigate the potential benefit of adding risedronate (R) to docetaxel (D) in patients with metastatic Castration Resistant Prostate Cancer (CRPC). PATIENTS AND METHODS: CRPC patients with bone metastasis were randomly assigned to receive D 75 mg/m(2) every 3 weeks and prednisone as first line chemotherapy, with or without R 30 mg oral once daily. The primary end-point was time to progression (TTP). A composite end-point of objective progression by RECIST criteria, PSA progression, or pain progression, whichever occurred first, was applied. The study had 80% power to detect an improvement of 30% in median TTP in the DR group (two-sided α=0.05). RESULTS: Five hundred and ninety-two men (301 D versus 291 DR) were randomised. TTP was 7.4 [D] versus 6.5 [DR] months (p=0.75). PSA and pain response rates were similar, 66.3% [D] versus 65.9% [DR] and 27.9% [D] versus 31.2% [DR], respectively. Median overall survival (OS) was 18.4 [D] versus 19.2 [DR] months (p=0.33). There were no differences in toxicity. CONCLUSION: The addition of the third generation bisphosphonate, risedronate, in the setting of effective first line docetaxel based chemotherapy did not increase efficacy, as indicated by the lack of improvement in TTP, OS, PSA- and pain response.

Prognostic factors and outcome in relapsed multiple myeloma after nonmyeloablative allo-SCT: a single center experience.

For relapsed multiple myeloma (MM) patients, allo-SCT is a possible treatment option, but recent data obtained using a nonmyeloablative (NMA) conditioning regimen are scarce. We retrospectively collected data from 38 relapsed MM patients who received a NMA allo-SCT from October 2001 to January 2008. In total, 18 patients (48%) were transplanted using a matched unrelated donor. The median follow-up is 2.3 years. In 16 patients (42%) the response improved and eight patients (21%) were rapidly progressive within 6 months after allo-SCT. In total, 15 patients (39%) were in CR after allo-SCT. The median PFS was 1.4 years (range, 0.1-4.9), and having a CR after allo-SCT or having chronic GVHD resulted in longer PFS. Median OS was 3.1 years (range, 0.2-7.2) and again having a CR after allo-SCT or chronic GVHD was associated with a better OS. Six patients (16%) have died from treatment-related diseases. These results indicate that NMA allo-SCT is a treatment option in relapsed MM patients and that results may be improved by strategies that enhance the CR rate after allo-SCT.

Extrapulmonary lymphangioleiomyomatosis: an unusual cause of biliary tract obstruction.

We present a patient who was diagnosed with retroperitoneal lymphangioleiomyomatosis (LAM) and who developed biliary tract obstruction caused by LAM in the papilla of Vater. After endoscopic retrograde cholangiopancreatography (ERCP) and papillotomy, the patient's liver enzymes normalised. Disease progression was slowed down with gosereline and interferon alpha 2b (IF N-alpha 2b). In patients with LAM and signs of biliary tract obstruction, disseminated LAM should be considered. IFN alpha 2b can be a useful treatment in patients with widespread LAM.

A breakthrough in cryosurgery.

Liver cryosurgery is one of the treatment options for unresectable liver metastases. Indications for the use of this treatment instead of classic surgery are bilobar disease, location of the tumor at an irresectable anatomic site, and comorbid conditions of the patient. Possible complications of cryosurgery are hemorrhage, coagulopathy, pneumonia, pleural effusion, abdominal abscess, and bile fistula. We describe a patient in whom a hepatobronchial fistula developed after cryosurgery. The patient had cryosurgery because of an unresectable liver metastasis in a Dukes' C rectal carcinoma. More details are given in the case report. To our knowledge, a hepatobronchial fistula as a complication of cryosurgery has never been reported. It therefore should be added to the list of possible cryosurgery complications.

Management of chemotherapy-induced adverse effects in the treatment of colorectal cancer.

The anticancer agents fluorouracil, raltitrexed, irinotecan and oxaliplatin show limited efficacy in the treatment of colorectal cancer and may be associated with substantial toxicity. Therefore, the prevention and reduction of chemotherapy-induced adverse effects is of major significance, in accordance with the increasing concern for the quality of life of patients with cancer. Therapeutic drug monitoring of fluorouracil and chronomodulation of fluorouracil and oxaliplatin, have been effective in reducing the incidence and gravity of adverse effects in several clinical trials. However, these concepts have not been implemented in clinical practice yet. At the present time, dose adaptation and supportive measures are the main tools for toxicity control in the treatment of colorectal cancer. In this review, supportive measures for alleviation of the adverse effects of fluorouracil, raltitrexed, irinotecan and oxaliplatin, respectively, are described, based on study results. The main adverse effects of these agents are myelosuppression, oral mucositis, diarrhoea, acute cholinergic syndrome, nausea and emesis, neurotoxicity, hand-foot syndrome and other cutaneous adverse effects, ocular toxicity, cardiotoxicity, small bowel toxicity, asthenia, elevated liver transaminase levels and alopecia. The incidence and gravity of these adverse effects are more or less related to the agent and administration schedule involved. The supportive measures and recommendations include the use of specific drugs, alterations of administration schedule and several nonpharmacological methods. In addition, guidelines for dosage adjustments when toxicity occurs are presented. For optimal management of adverse effects, patients should be considered individually, while patients, nurses and physicians should cooperate to identify and treat adverse effects in an early stage of their development.

Risk factors determining chemotherapeutic toxicity in patients with advanced colorectal cancer.

Antitumour therapy in advanced colorectal cancer has limited efficacy. For decades, fluorouracil has been the main anticancer drug for the treatment of colorectal cancer. Recently, however, new agents have been introduced: raltitrexed, irinotecan and oxaliplatin. Currently, the dosage for an individual patient is calculated from the estimated body surface area of the patient. Toxicity, however, frequently necessitates decreasing the dosage, extending the dose interval or even discontinuing treatment. Risk factors with predictive value for toxicity have been identified in several studies. These risk factors are often determined by the pharmacokinetic and pharmacodynamic properties of the drug. In this review, the risk factors for toxicity of the cytotoxic agents used in the treatment of advanced colorectal cancer are considered. For fluorouracil, age, gender, performance status, genetic polymorphism of dihydropyridine dehydrogenase, drug administration schedule, circadian rhythm of plasma concentrations, history of previous chemotherapy-related diarrhoea, xerostomia, low neutrophil levels, and drug-drug interactions have been identified as affecting chemotherapeutic toxicity. For raltitrexed, gender and renal and hepatic impairment, and for oxaliplatin, renal impairment and circadian rhythm of plasma concentrations, respectively, can be considered as risk factors for toxicity. In addition, age, performance status, bilirubinaemia, genetic polymorphism of uridine 5'-diphosphate-glucuronyltransferase-1A1 and drug administration schedule have been shown to be related to irinotecan toxicity. The available literature suggests that dose adjustment based on these risk factors can be used to individualise the dose in order to decrease toxicity and to improve the therapeutic index. This also applies to therapeutic drug monitoring, which has been shown to be effective controlling the toxicity of fluorouracil in some studies. Future research is warranted to assess the potential advantage of dose individualisation of chemotherapy founded on risk factors, over direct dose calculation from the estimated body surface area, with regard to toxicity, therapeutic index, and quality of life, in patients with advanced colorectal cancer.

Relationship between soluble transferrin receptors in serum and membrane-bound transferrin receptors.

The expression of transferrin receptors on the cell membrane of erythroblasts was analysed with flow cytometry in patients with different forms of anaemia. At the same time the concentration of soluble transferrin receptors (sTfRs) was analysed in serum. It was shown that only in iron deficiency a high concentration of sTfRs in serum could be explained with an increased expression of transferrin receptors on the erythroblastic membrane. In anaemia of chronic disease and myelodysplasia a discrepancy between a low expression on the cell membrane and normal or elevated serum values was seen. From this study we conclude that the concentration of sTfRs in serum does not only depend on the expression of transferrin receptors on the erythroblasts but also on the erythroid activity.

Primary liver cancer in two sisters in Holland with intermittent acute porphyria.

Two sisters living in Holland, with a niece now living in South Africa, were reported in 1958 to have inherited intermittent acute porphyria (IAP). In 1994 both sisters died from primary liver cancer. Other reports have also noted an increased mortality from carcinoma of the liver in porphyrics. Porphyria variegata has a high prevalence in white and coloured South Africans, and it would be relatively easy to ascertain whether those who have inherited the gene for this disorder, in South Africa, have a higher than reported mortality from liver cancer. If they do, consideration should be given to ways to reduce their risk of developing and dying from this cancer.

Dose intensity of standard adjuvant CMF with granulocyte colony-stimulating factor for premenopausal patients with node-positive breast cancer.

The effects of granulocyte colony-stimulating factor (G-CSF) on total dose and dose intensity of standard oral adjuvant CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy were studied in premenopausal patients with node-positive breast cancer. Treatment consisted of standard CMF and locoregional radiotherapy (on indication). G-CSF was administered if the leukocyte count recovery was insufficient. Fifty-one patients required no G-CSF ("no cytopenia'), and 50 patients received G-CSF ("G-CSF). Twenty-two patients, however, received no G-CSF support despite insufficient leukocyte recovery ("control'). Following G-CSF, leukocyte recovery was adequate in 83% of the chemotherapy cycles. The proportion of the patients who had a dose intensity > or = 85% was 90% in the "no cytopenia' group, 74% in the "G-CSF' group, and 45% in "control' group (p < 0.05). Leukocyte recovery was adequate in 87% of the chemotherapy cycles in the patients who received radiotherapy as compared with 92% of those in the patients without radiotherapy (p < 0.05). In conclusion an adequate leukocyte recovery after G-CSF was found in 83% of all chemotherapy cycles. The dose intensity of the G-CSF group was higher as compared with controls. The impact of radiotherapy on hematological recovery was significant, but not dependent on G-CSF.

Lobular panniculitis after subcutaneous administration of interleukin-2 (IL-2), and its exacerbation during intravenous therapy with IL-2.

Interleukin-2 (IL-2) is now registered for the treatment of renal cell carcinoma in a number of European countries. The subcutaneous (sc) route of administration is being used increasingly because of its better toxicity profile compared with higher dose intravenous (iv) protocols. We report here a patient who developed a lobular panniculitis at the site of sc IL-2 injection which prevents continuation of sc therapy. Subsequent administration of the same IL-2 dose by iv injection caused recurrence of the problem again necessitating discontinuation of IL-2 treatment.

Quantitative determination of non-haem iron and ferritin iron in bone marrow using flameless atomic absorption spectrophotometry. A comparative study on the cytological and chemical determination of the bone marrow iron content.

A method for non-haem iron analysis in bone marrow aspirates using graphite furnace atomic absorption spectrophotometry has been developed. Bone marrow aspirates were obtained from patients with various disorders. A good correlation is observed between chemical and cytological assessment of total non-haem iron in bone marrow. An intra-assay coefficient of variation of 9.0% was observed. The ferritin-iron concentration was also determined and a CVduplo of 11% was found. The ferritin iron concentration increased with an increasing total iron content until saturation of ferritin appeared to be reached at about 3 g ferritin per kg protein. It was concluded that the quantitative determination of bone marrow iron can be of value in the diagnosis and investigation of both hypo- and hyper-ferraemic disorders.

Measurements of serum ferritin used to predict concentrations of iron in bone marrow in anemia of chronic disease.

We determined serum ferritin, C-reactive protein (CRP), fibrinogen, and the erythrocyte sedimentation rate (ESR) in 73 patients with anemia of chronic disease. Nomograms of CRP, ESR, or fibrinogen vs ferritin concentrations were constructed and used to estimate the iron store in bone marrow. Iron stores estimated from the nomograms were compared with the results of staining cytological bone marrow smears for iron, the reference method for evaluating iron in bone marrow. In contrast to the results of Witte et al. (Clin Chem 1985;31:1011; Am J Clin Pathol 1986;85:202-6 and 1988;90:85-7), we observed that nomograms of CRP, fibrinogen, or ESR (i.e., acute-phase reactants not influenced by changes in iron metabolism) vs ferritin are not suitable to correct for the acute-phase component of changes in ferritin concentrations. For ferritin concentrations less than 70 micrograms/L, we found that iron deficiency, as judged from bone marrow iron stain, apparently was always present.

A patient with probable systemic lupus erythematosus, lupus anticoagulant and myocardial infarction.

The case history of a 31-year-old woman is described. She had a history of thrombosis; in the past there had been an arterial embolus of the left superficial femoral artery and venous thrombosis of the right leg. The patient was admitted to hospital because of fever of unknown origin. During the hospital stay the diagnosis of probable SLE was made. She died of myocardial infarction. At autopsy, thrombosis of the small arterioles of the heart was found without sclerosis of the coronary arteries. A lupus anticoagulant could be demonstrated in her blood and seems to have been the cause of this rare complication. Treatment with anticoagulants is advised for patients with LAC and a history of thrombosis.