A randomised study of tailored toxicity-based dosage of fluorouracil-epirubicin-cyclophosphamide chemotherapy for early breast cancer (SBG 2000-1).

STUDY AIM: Retrospective studies have demonstrated a worse outcome in breast cancer patients not developing leukopenia during adjuvant chemotherapy. The SBG 2000-1 is the first randomised trial designed to compare individually dosed chemotherapy without G-CSF support based on grade of toxicity to standard-dosed chemotherapy based on body surface area (BSA). METHODS: Patients with early breast cancer were included and received the first cycle of standard FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2). Patients with nadir leukopenia grade 0-2 after first cycle were randomised between either 6 additional courses of tailored FEC with increased doses (E 75-90 mg/m2, C 900-1200 mg/m2) or fixed treatment with 6 standard FEC. Patients with grade 3-4 leukopenia were registered and treated with 6 standard FEC. Primary end-point was distant disease-free survival (DDFS). RESULTS: The study enrolled 1535 patients, of which 1052 patients were randomised to tailored FEC (N = 524) or standard FEC (N = 528), whereas 401 patients with leukopenia grade 3-4 continued standard FEC and formed the registered cohort. Dose escalation did not statistically significantly improve 10-year DDFS (79% and 77%, HR 0.87, CI 0.67-1.14, P = 0.32) or OS (82% and 78%, respectively, HR 0.89, CI 0.57-1.16, P = 0.38). Corresponding estimates for the registered group of patients were DDFS 79% and OS 82%, respectively. CONCLUSIONS: The SBG 2000-1 study failed to show a statistically significant improvement of escalated and tailored-dosed chemotherapy compared with standard BSA-based chemotherapy in patients with low haematological toxicity, although all efficacy parameters showed a numerical advantage for tailored treatment.

CA125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use.

CA125 is currently the most widely used tumor marker for ovarian epithelial cancer. The aim of this article is to provide guidelines for the routine clinical use of CA125 in patients with ovarian cancer. Due to lack of sensitivity for stage I disease and lack of specificity, CA125 is of little value in the detection of early ovarian cancer. At present, therefore, CA125, either alone or in combination with other modalities, cannot be recommended for screening for ovarian cancer in asymptomatic women outside the context of a randomized controlled trial. Preoperative levels in postmenopausal women, however, may aid the differentiation of benign and malignant pelvic masses. Serial levels during chemotherapy for ovarian cancer are useful for assessing response to treatment. Although serial monitoring following initial chemotherapy can lead to the early detection of recurrent disease, the clinical value of this lead-time is unclear. CA125 is the ovarian cancer marker against which new markers for this malignancy should be judged.

Serum tumor marker CA 125 for monitoring ovarian cancer during follow-up.

CA 125 is currently widely applied in the management of patients with ovarian cancer. However, a change in results of CA 125, which should be considered significant, has not been defined. The aim of this study was to investigate the ability of CA 125 to signal progressive ovarian cancer during follow-up after first-line chemotherapy. The study patients were selected retrospectively among 255 patients with stage IC-IV ovarian cancer. The evaluation of the CA 125 information was based on the analytical imprecision, the normal intra-individual biological variation, the sampling interval, and the cut-off value. Additionally, the utility of a new assessment criterion based upon an increment of 2.5 times the baseline CA 125 concentration confirmed by a third measurement was investigated. The efficiency of CA 125 to identify progression and non-progression during follow-up varied between 76.5 and 79.9%, depending on the applied time limit for an acceptable positive lead time. The median lead time for true positive results was 95-99.5 days. Using the new elaborated criterion, the efficiency of CA 125 for identifying progression and non-progression varied between 75.7 and 78.5%, depending on the applied time limit for an acceptable positive lead time. The median lead time for true positive results was 91-95.5 days. CA 125 provided early and reliable information about progressive disease during follow-up. The applied criteria can therefore be recommended in further studies assessing the clinical utility of serological tumor markers in patients with ovarian cancer.

Interpretation of sequential measurements of cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), and tissue polypeptide antigen (TPA) based on analytical imprecision and biological variation in the monitoring of ovarian cancer.

The main objective with cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), and tissue polypeptide antigen (TPA) monitoring of ovarian cancer patients is to detect an early change of disease activity with high reliability. We hypothesized that a monitoring scheme for ovarian cancer patients with serological tumor markers should take into account the stochastic variation, i.e. the probability that observed increases and decreases may solely be due to analytical imprecision and normal intra-individual biological variation. The aim of this study was to provide a detailed characteristic of the within-subject mean steady state concentrations and the associated variability in healthy individuals with an age distribution representative for ovarian cancer patients. Thirty-one healthy women with a median age of 55 years comprised the study population. Sixteen blood samples were collected from each subject in four series, with four samples per series, over a period of approximately 1 year. We found that, i) natural logarithmic-transformed concentrations were more homogeneously distributed between individuals than the original concentrations, ii) the within-subject mean steady state levels, the standard deviations, and the coefficients of variation differed among subjects, and iii) the steady state variability differed among the markers. In conclusion, our data indicate that the assessment of sequential CA 125, CEA, and TPA concentrations is more complex than hitherto recognized. We suggest that it is necessary to adjust the assessment criteria to the type of marker, and that assessment may be facilitated if based on natural logarithmic transformed concentrations.

Serum tumour marker CA 125 in monitoring of ovarian cancer during first-line chemotherapy.

The value of the serum tumour marker CA 125 to date has been in the monitoring of ovarian cancer patients for response to therapy and for recurrence of disease. However, despite the availability of serial data on CA 125, the problem of interpreting a change over time is still unsolved. The aim of this study was to assess the ability of CA 125 to monitor patients with ovarian cancer during postoperative chemotherapy. 255 patients with stage IC-IV ovarian cancer were allocated to the tumour marker monitoring study. The evaluation of CA 125 information was based on the analytical imprecision, the normal intra-individual biological variation, the sampling interval, and the cut-off value. Additionally, a new assessment criterion based upon an increment of 2.5 times the baseline CA 125 concentration confirmed by a third measurement was elaborated and the utility investigated. The efficiency of CA 125 for identifying progression and non-progression during first-line chemotherapy was 91.9%. The median lead time for true positive results was 41 days. Using the new elaborated criterion the efficiency of CA 125 for identifying progression and non-progression during first-line chemotherapy was 90.5%. The median lead time for true positive results was 35 days. CA 125 gave reliable prediction of progressive disease during postoperative chemotherapy. The results indicate a high applicability of the presented progression criteria during CA 125 monitoring of patients with changing activity of ovarian cancer.

Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer.

PURPOSE: To determine the side effects and feasibility of cisplatin and carboplatin each in combination with paclitaxel as front-line therapy in advanced epithelial ovarian cancer. PATIENTS AND METHODS: Patients were randomly allocated to receive paclitaxel 175 mg/m(2) intravenously as a 3-hour infusion followed by either cisplatin 75 mg/m(2) or carboplatin (area under the plasma concentration-time curve of 5), both on day 1. The schedule was repeated every 3 weeks for at least six cycles. Women allocated to paclitaxel-cisplatin were admitted to the hospital, whereas the carboplatin regimen was administered to outpatients. RESULTS: A total of 208 eligible patients were randomized. Both regimens could be delivered in an optimal dose and without significant delay. Paclitaxel-carboplatin produced significantly less nausea and vomiting (P: <.01) and less peripheral neurotoxicity (P: =.04) but more granulocytopenia and thrombocytopenia (P: <.01). The overall response rate in 132 patients with measurable disease was 64% (84 of 132 patients), and in patients with elevated CA 125 levels at start, it was 74% (132 of 178 patients). With a median follow-up time of 37 months, the median progression-free survival time of all patients was 16 months and the median overall survival time was 31 months. The small number of patients entered onto the study caused wide confidence intervals (CIs) around the hazards ratio for progression-free survival of paclitaxel-carboplatin compared with paclitaxel-cisplatin (hazards ratio, 1.07; 95% CI, 0.78 to 1.48) and did not allow conclusions about efficacy. CONCLUSION: Paclitaxel-carboplatin is a feasible regimen for outpatients with ovarian cancer and has a better toxicity profile than paclitaxel-cisplatin.

Biological variation and analytical imprecision of CA 125 in patients with ovarian cancer.

Despite the availability of serial data on CA 125 in ovarian cancer, the problem of interpreting a change over time is still unsolved. Changes in marker concentrations are due not only to patients improving or deteriorating but also to analytical imprecision and normal intra-individual biological variation. The aim of this study was to assess the analytical imprecision (CV(A)) and the intra- and inter-individual biological variation (CV(I) and CV(G), respectively) of CA 125 in a group of 26 patients with clinically stable ovarian cancer. Furthermore, the critical difference for a change between two consecutive CA 125 concentrations calculated as square root(2) x Z x (CV(A)2 + CV(I)2)(1/2) (Z =1.65 for unidirectional and 1.96 for bidirectional changes, p < or = 0.05) and the index of individuality calculated as ((CV(A)2+CV(I)2)/CV(G)2)(1/2) were estimated. After the exclusion of outliers, CV(A) and the average CV(I) and CV(G) were 12.1%, 24.0%, and 43.1%, respectively. The index of individuality was 0.62 and the critical difference calculated for unidirectional changes was 62.6%. CV(A) and CV(I) contribute considerably to the variation in serial results and should, therefore, be included in the criteria for serum tumor marker assessment during monitoring of patients with ovarian cancer. The cut-off value of CA 125 is of minor value in detecting unusual results for an individual subject, when previous measurements from an individual are available. These measurements should be preferred as reference for interpretation of new results.

Assessment of biological variation and analytical imprecision of CA 125, CEA, and TPA in relation to monitoring of ovarian cancer.

OBJECTIVES: Changes in serial tumor marker results during monitoring of patients with ovarian cancer are due not only to deterioration or amelioration of the patient's condition, but also to preanalytical sources of variation (CPP), total random analytical error, and within-subject normal biological variation. The aim of the study was to assess (i) the analytical imprecision (CVA) and the average inherent intra- and interindividual biological variation (CVTI and CVG, respectively) for CA 125, CEA, and TPA in a group of healthy women; (ii) the significance of changes in serial results of each marker; and (iii) the index of individuality. METHODS: The study group consisted of 31 healthy women. Sixteen blood samples from each subject were collected in four series over a period of approximately 1 year. Data analysis was based on ANOVA. The index of individuality was calculated as ((CV2A + CV2TI)/CV2G)1/2 and the critical difference for a change between two consecutive concentrations as radical2xZx(CV2P + CV2A + CV2TI)1/2 (Z = 1.65 for unidirectional and 1.96 for bidirectional changes, P

Gemcitabine in the treatment of ovarian cancer.

Gemcitabine is a new nucleoside antimetabolite with established activity against solid tumours. In previously treated patients the response rate with the drug alone was around 13%. Combination therapy with gemcitabine-cisplatin or gemcitabine-paclitaxel induced responses in 53 and 40% respectively. In previously untreated patients with poor prognostic features a 24% response rate was reported for the drug alone, but in combination with cisplatin remissions were found in 53%-71% of patients. Gemcitabine, paclitaxel, and carboplatin (or cisplatin) in combination appeared to be a feasible and active combination. In a pilot with eight previously treated patients all obtained a remission and in untreated patients a remission occurred in all evaluable patients either clinically or measured by a decrease of CA 125. Dose-limiting toxicity is mainly haematological.

Paclitaxel (175 mg/m2 over 3 hours) with cisplatin or carboplatin in previously untreated ovarian cancer: an interim analysis.

The side effects of cisplatin (75 mg/m2) in combination with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (175 mg/m2 over 3 hours) are expected to be more severe and frequent than those of carboplatin (area under the concentration-time curve of 5) in combination with the same dose of paclitaxel, but the combinations are expected to be equally effective. A disadvantage of the cisplatin-based regimen is that patients need to be admitted to the hospital. The carboplatin regimen can be administered to outpatients. We tested both combinations administered every 3 weeks in a randomized phase III study in patients with previously untreated epithelial ovarian cancer. An interim analysis for toxicity was performed in 145 patients shortly after study closure. We observed a difference in the incidence of nausea, vomiting, and neurotoxicity favoring the women treated with the carboplatin regimen, but this regimen caused more myelotoxicity. Maturation of the study is awaited before survival data can be analyzed and final conclusions can be drawn.

The role of second-look laparotomy in the long-term survival in ovarian cancer.

BACKGROUND: To elucidate the role of second-look laparotomy in the management of ovarian cancer patients, were retrospectively reviewed our experience with this procedure in epithelial ovarian cancer patients. PATIENTS AND METHODS: The hospital records of 617 patients with advanced ovarian cancer were reviewed. The 308 patients who underwent second-look laparotomy were followed from four to 18 years with a median follow-up of 12 years after start of primary chemotherapy. RESULTS: Patients who achieved pathological complete response (PCR), microscopic partial response (PPR mic.), macroscopic partial response (PPR mac.), stable disease (PSD), and progressive disease (PPD) at second-look laparotomy had a median survival time of 149, 39.5, 24, 14, and eight months, respectively. Secondary surgical cytoreduction could be performed only in 101 patients with macroscopic persistent disease. The group of all patients with secondary tumor debulking had no survival advantage compared with the group of patients with PPR mac., PSD, and PPD, unable to have secondary cytoreduction. Patients left with no tumor after second-look laparotomy did not survive as long as patients who achieved PCR and PPR mic. at second-look laparotomy. Factors prolonging survival after second-look laparotomy included younger age, good pre-treatment performance status, smaller primary residual tumor size, longer interval between start of chemotherapy and second-look laparotomy, and the pathologically proven CR or PR mic. CONCLUSION: Second-look laparotomy appears to have a minor role in the routine management of ovarian cancer patients, especially in the context of the limited effectiveness of second-line therapy. This procedure should be limited to clinical treatment protocols to determine effectiveness of new agents.

Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study.

BACKGROUND: Many studies have shown that CA 125 levels frequently rise prior to clinical evidence of progression of ovarian cancer. For clinical trials an accepted definition of progression according to CA 125 is required. We therefore determined what change in CA 125 level was the most accurate predictor of relapse in patients on follow up after therapy for ovarian cancer. PATIENTS AND METHODS: Serial CA 125 levels were studied from 255 patients entering the North Thames Ovary Trial of 5 versus 8 courses of chemotherapy. An initial analysis was made 2 months after closure of the trial, a more detailed analysis was made after 81 confirmed relapses among evaluable patients and a final analysis was made one year later with longer follow-up. RESULTS: On the basis of the results from the interim analyses and the cut-off level of 22-35 U/ml used by different laboratories, 30 U/ml was chosen as the upper limit of normal. In the final analysis a doubling of CA 125 from the upper limit of normal was defined as progression. Using this method sensitivity was 85.9%, specificity 91.3%, positive predictive value 94.8%, and negative predictive value was 77.8%. Insisting on a confirmatory elevated CA 125 level reduced the false positive rate to < 2% with a sensitivity of 83.9%. The median lead-time prior to clinical progression was 63 days. CONCLUSION: A confirmed rise of serum CA 125 level to more than twice the upper limit of normal during follow up after first line chemotherapy accurately predicts tumour relapse.

Second-look laparotomy in the management of patients after radical surgery for ovarian cancer.

BACKGROUND: Radically excised ovarian cancers present an unsolved problem with regard to the value of routine second-look operation. This study presents the outcome of second-look operations in an effort to help elucidate this problem. PATIENTS AND METHODS: Twenty-eight patients who underwent radical surgery for ovarian cancer stage IC-IIIA were given adjuvant chemotherapy with cyclophosphamide 500 mg/m2 i.v., adriamycin 40 mg/m2 i.v. and 5-fluorouracil 500 mg/m2 i.v., all administered on days 1 and 8 every 4 weeks until achievement of a cumulative adriamycin dose of 400 mg/m2. It was planned that second-look laparotomy would be performed 10-12 months after the primary operation. RESULTS: Four of 28 patients (14.3%) had positive findings at second-look laparotomy. Two of these 4 patients had only microscopic disease, and after second-line chemotherapy including cisplatin one of them is clinically free of tumor 50 months after the primary operation. Two of 28 patients had clinical recurrences before the planned second-look operation. Four of the 22 patients (18.2%) with negative second-look operations developed recurrent disease within a median time of 12 months later. The 5-year survival rate for all 28 patients was 67%. CONCLUSION: Although a small group of patients may benefit from a strategy that includes delayed second-look operation, we conclude that this should not be a routine procedure in the management of patients who undergo radical surgery for ovarian cancer.

[Focal myositis]. / Myositis focalis.

Focal myositis is a rare benign pseudotumor of skeletal muscle, of unknown cause. Clinically it presents as an enlarging mass within a muscle, usually in en extremity. Biopsy shows characteristic histological changes of inflammation, focal degeneration and regeneration. The natural course of this disorder is spontaneous regression. This report describes the case of a 17-year-old boy with focal myositis of the thigh and a review of the relevant literature.

[Poisoning by kidney beans (Phaseolus vulgaris)]. / Forgiftning med kidneybønner (Phaseolus vulgaris).

During recent years, numerous new and exotic fruits have become available in Denmark. However, some of these may be potentially hazardous if incorrectly prepared. Some leguminous plants, in particular, contain considerable amounts of toxic lectins. The authors report two persons who developed severe symptoms of poisoning including diarrhoea, vomiting, muscular pain, rhabdomyolysis and toxic myocarditis after consuming raw and insufficiently cooked kidney beans (Phaseolus vulgaris). Meticulous instructions about handling should accompany the sale of potentially hazardous vegetables such as these.