Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials.

BACKGROUND: Neoadjuvant chemotherapy improves outcome in osteosarcoma. Determination of optimum regimens for survival, toxicity and prognostic factors requires randomised controlled trials to be conducted. PATIENTS AND METHODS: Between 1983 and 2002, the European Osteosarcoma Intergroup recruited 1067 patients with localised extremity osteosarcoma to three randomised controlled trials. Standard treatment in each was doxorubicin 75 mg/m(2) and cisplatin 100 mg/m(2). Comparators were addition of methotrexate (BO02/80831), a multidrug regimen (BO03/80861) and a dose-intense schedule (BO06/80931). Standard survival analysis methods were used to identify prognostic factors, temporal and other influences on outcome. RESULTS: Five- and 10-year survival were 56% (95% confidence interval 53% to 59%) and 52%, respectively (49% to 55%), with no difference between trials or treatment arms. Median follow-up was 9.4 years. Age range was 3-40 years (median 15). Limb salvage was achieved in 69%. Five hundred and thirty-three patients received the standard arm, 79% completing treatment. Good histological response to preoperative chemotherapy, distal tumour location (all sites other than proximal humerus/femur) and female gender were associated with improved survival. CONCLUSIONS: Localised osteosarcoma will be cured in 50% of patients with cisplatin and doxorubicin. Large randomised trials can be conducted in this rare cancer. Failure to improve survival over 20 years argues for concerted collaborative international efforts to identify and rapidly test new treatments.

Factors influencing catheter-related infections in the Dutch multicenter study on high-dose chemotherapy followed by peripheral SCT in high-risk breast cancer patients.

Neutropenia following high-dose chemotherapy leads to a high incidence of infectious complications, of which central venous catheter-related infections predominate. Catheter-related infections and associated risk factors in 392 patients participating in a randomized adjuvant breast cancer trial and assigned to receive high-dose chemotherapy and peripheral stem-cell reinfusion were evaluated. Median catheter dwell time was 25 days (range 1-141). Catheter-related infections were seen in 28.3% of patients (11 infections per 1000 catheter-days). Coagulase-negative staphylococci were found in 104 of 186 positive blood cultures (56%). No systemic fungal infections occurred. Cox regression analysis showed that duration of neutropenia >10 days (P=0.04), using the catheter for both stem-cell apheresis and high-dose chemotherapy (P= <0.01), and use of total parenteral nutrition (TPN, P=0.04) were predictive for catheter-related infections. In conclusion, a high incidence of catheter-related infections after high-dose chemotherapy was seen related to duration of neutropenia, use of the catheter for both stem-cell apheresis and high-dose chemotherapy, and use of TPN. Selective use and choice of catheters could lead to a substantial reduction of catheter-related infectious complications.

Continuous versus intermittent tamoxifen versus intermittent/alternated tamoxifen and medroxyprogesterone acetate as first line endocrine treatment in advanced breast cancer: an EORTC phase III study (10863).

BACKGROUND: Continuous ligand depletion of endocrine responsive tumours may enhance resistance to therapy. Intermittent treatment with tamoxifen (T) was considered to mimic (incomplete) ligand depletion and reintroduction. Furthermore it was postulated that alternating tamoxifen with a non-cross resistant endocrine modality could (further) postpone hormone resistance. PATIENTS AND METHODS: Postmenopausal patients with advanced breast cancer who did not progress after 4 months of first line T therapy were randomised to continue T (40 mg daily) or to 2 monthly intermittent T or intermittent/alternated T and medroxyprogesterone acetate (MPA, 300 mg daily). At progression during break or during MPA, T should be reintroduced. Endpoints of the study were progression free survival (PFS), time to resistance to tamoxifen and overall survival (OS). RESULTS: Of 593 registered patients, 276 were randomised. After 8 years follow-up the median PFS for continuous T, intermittent T and intermittent/alternated T and MPA was 11.0 (8.1-15.2), 8.0 (6.2-12.4) and 10.8 (7.1-16.7) months, respectively (NS). Resistance to tamoxifen was established only in 84%, 70% and 55% of patients in the three treatment arms, respectively. The median times from randomisation to resistance to tamoxifen were 12.5 (9.1-21.1), 13.2 (8.8-19.8) and 24.0 (16.9-60.9) months, respectively (p<0.001), without translation in differences in survival times. CONCLUSION: Intermittent T or intermittent/alternated T and MPA had no impact on PFS or OS as compared with classical continuous T in patients with advanced breast cancer. Intermittent/alternated T and MPA resulted in prolonged time to resistance to T, but this might partly be due to bias by omittance of the proof of tamoxifen resistance in a high proportion of the patients in this treatment arm.

Polymorphisms in the large subunit of human RNA polymerase II as target for allele-specific inhibition.

The lack of specificity of cancer treatment causes damage to normal cells as well, which limits the therapeutic range. To circumvent this problem one would need to use an absolute difference between normal cells and cancer cells as therapeutic target. Such a difference exists in the genome of all individuals suffering from a tumor that is characterized by loss of genetic material [loss of heterozygosity (LOH)]. Due to LOH, the tumor is hemizygous for a number of genes, whereas the normal cells of the individual are heterozygous for these genes. Theoretically, polymorphic sites in these genes can be utilized to selectively target the cancer cells with an antisense oligonucleotide, provided that it can discriminate the alleles and inhibit gene expression. Furthermore, the targeted gene should be essential for cell survival, and 50% gene expression sufficient for the cell to survive. This will allow selective killing of cancer cells without concomitant toxicity to normal cells. As an initial step in the experimental test of this putative selective cancer cell therapy, we have developed a set of antisense phosphorothioate oligonucleotides which can discriminate the two alleles of a polymorphic site in the gene encoding the large subunit of RNA polymerase II. Our data show that the exact position of the antisense oligonucleotide on the mRNA is of essential importance for the oligo-nucleotide to be an effective inhibitor of gene expression. Shifting the oligonucleotide position only a few bases along the mRNA sequence will completely abolish the inhibitory activity of the antisense oligonucleotide. Reducing the length of the oligonucleotides to 16 bases increases the allele specificity. This study shows that it is possible to design oligonucleotides that selectively target the matched allele, whereas the expression level of the mismatched allele, that differs by one nucleotide, is only slightly affected.

Diabetes insipidus and adrenal insufficiency in a patient with metastatic breast cancer.

A patient previously treated for bilateral breast cancer with mastectomy, radiation therapy and in remission on hormonal therapy for more than five years presented with abdominal symptoms from breast cancer relapse. She developed inappropriate polyuria and hypernatraemia, which responded to desmopressin. In combination with the absence of a high signal from the posterior lobe of the pituitary on MRI , these data indicated the presence of partial central diabetes insipidus. The anterior pituitary showed partial failure (low follicle-stimulating hormone, luteinising hormone and insulin-like growth factor-1 levels). Furthermore, primary adrenal insufficiency had developed, ascribed to bilateral tumour invasion of the adrenals. This rare combination of endocrinological failures in a patient with metastatic breast cancer is discussed.

Corticosteroids significantly delay the onset of docetaxel-induced fluid retention: final results of a randomized study of the European Organization for Research and Treatment of Cancer Investigational Drug Branch for Breast Cancer.

PURPOSE: To confirm the efficacy of docetaxel in patients with breast cancer previously treated with one chemotherapy regimen for advanced or metastatic disease and to compare the incidence of fluid retention (FR) and skin toxicity when docetaxel is administered with and without prophylactic corticosteroids. PATIENTS AND METHODS: Eighty-three patients, pretreated with one chemotherapy regimen for metastatic breast cancer (MBC) with bidimensionally measurable and progressive disease, were eligible for this randomized trial. Docetaxel with prophylactic oral antihistamine was administered at a dose of 50 mg/m2 as a 1-hour infusion on days 1 and 8 every 21 days and patients were randomized to receive methylprednisolone (40 mg days -1, 0, 1, 7, 8, and 9 of each cycle) (arm A) or no methylprednisolone (arm B). RESULTS: Twenty-eight patients (34%, 95% confidence interval [CI], 23% to 45%) achieved on objective response. The median time to disease progression and median overall survival time were 5 and 13.5 months, respectively. In total, 415 cycles of docetaxel were administered (arm A: N = 219, median = six; arm B: N = 196, median = five). The most common toxicity observed was grade 3 or 4 neutropenia, which occurred in 79% of patients. Clinically significant nonhematologic side effects included skin reactions and asthenia. In an intent-to-treat analysis, patients who received methylprednisolone premedication had a delayed onset of FR (median time to onset of FR: arm A, 84 days; arm B, 62 days; P = .01) and received a higher median cumulative dose of docetaxel before the onset of FR (arm A, 333 mg/m2; arm B, 215 mg/m2; P = .001). There was no statistically significant difference in the incidence of skin toxicity between the two arms. CONCLUSION: Docetaxel, at this dose and schedule, has definite antitumor activity in pretreated MBC patients. Moreover, this is the first randomized trial to show that corticosteroids have a favorable impact on docetaxel-induced FR.

Neoadjuvant chemotherapy with doxorubicin and cisplatin in malignant fibrous histiocytoma of bone: A European Osteosarcoma Intergroup study.

PURPOSE: Studies involving small case series have suggested that malignant fibrous histiocytoma of bone (MFH-B) is a chemosensitive tumor and that chemotherapy may improve survival. In this study, we evaluated clinical and pathologic response rates and survival in a series of patients treated with a consistent chemotherapy regimen of doxorubicin and cisplatin (DOX/DDP). PATIENTS AND METHODS: Study patients were required to have biopsy-proven MFH-B, no previous chemotherapy, and primary or metastatic measurable disease and to be /= 90% necrosis). Median time to progression was 56 months, and the 5-year progression-free survival rate was 56% (95% confidence interval [CI], 40% to 72%). Median survival time was 63 months, and the 5-year survival rate was 59% (95% CI, 41% to 77%). Patients with a good pathologic response had longer survival times and times to progression than did those with a poor response. Also treated were two patients with locally recurrent and nine with metastatic disease, and these patients had a median survival time of 17.5 months. CONCLUSION: Our study suggests that adjuvant or neoadjuvant chemotherapy with DOX/DDP is beneficial in MFH-B. Good pathologic response rates and survivals are quite comparable with those for osteosarcoma, a related bone tumor for which adjuvant or neoadjuvant chemotherapy is an accepted practice.

Doxorubicin and cisplatin chemotherapy in high-grade spindle cell sarcomas of the bone, other than osteosarcoma or malignant fibrous histiocytoma: a European Osteosarcoma Intergroup Study.

There are limited data that define the role of chemotherapy in the treatment of high-grade spindle cell sarcomas of bone, other than osteosarcoma or malignant fibrous histiocytoma (MFH-B). This prospective study evaluates the effect of doxorubicin and cisplatin on these tumours. Thirty-seven patients, age 65 years, with spindle cell sarcoma of bone, except osteosarcoma or MFH-B, were included. Chemotherapy consisted of doxorubicin and cisplatin every 3 weeks for six cycles. Resection was performed after three cycles. In 15 patients with metastases, response assessment showed three complete responses (CR), four stable disease (SD), five progression; three were not evaluable. Median time to progression was 30 months (95% Confidence Interval (CI), 8-51 months) for the operable non-metastatic patients; median survival 41 months (95% CI, 16-82 months). Median time to progression in the metastatic group was 10 months (95% CI, 0-18 months) and median survival was 14 months (95% CI, 4-45 months). This study suggests a limited role for doxorubicin and cisplatin in metastatic high-grade spindle cell sarcoma of bone, other than osteosarcoma or MFH-B cases.

Survival of patients with ovarian cancer due to a mismatch repair defect.

PURPOSE: Hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome) is characterized by the development of cancer of the colorectum, endometrium and other cancers. Cancer of the ovaries (OC) has frequently been reported in HNPCC. Colorectal cancer associated with HNPCC has a better survival chance compared to sporadic colorectal cancer. It is yet unknown whether patients with OC from HNPCC families (OC-HNPCC) also have a better survival. Therefore, the aim of the study was to compare the survival between patients with OC-HNPCC and a control group. METHODS: A total of 26 patients with OC were identified from the Dutch HNPCC Registry. A control group (52 cases) matched for age, stage and year of diagnosis was derived from the population-based Eindhoven Cancer Registry. Data on treatment were collected for all patients. Kaplan-Meier analysis was used to calculate the crude survival. RESULTS: The mean age at diagnosis of OC-HNPCC was significantly lower than the age of sporadic OC (49.5 vs 60.9 years). Compared to sporadic OC, OC-HNPCC was diagnosed at an earlier stage. The survival rate was not significantly different between patients with OC-HNPCC and the controls with sporadic OC. The cumulative 5-year-survival rates were 64.2 and 58.1% respectively. CONCLUSION: On the basis of our findings, we recommend to treat OC-HNPCC similar to sporadic OC.

Phase II study of carboplatin in patients with advanced or recurrent endometrial carcinoma. A trial of the EORTC Gynaecological Cancer Group.

The aim of this study was to investigate the efficacy and toxicity of carboplatin given as monotherapy in endometrial adenocarcinoma. Cisplatin is one of the most active drugs in gynaecological cancer types, but at the cost of an associated high toxicity. In this high-risk population of endometrial cancer patients, it is necessary to have chemotherapy regimens with a low toxicity. Patients eligible for this study were those with histologically-confirmed endometrial adenocarcinoma with evidence of recurrent and/or metastatic disease. Carboplatin was administered every 4 weeks as a first- (dose: 400 mg/m(2)) or second- (dose: 300 mg/m(2)) line chemotherapy. Of the 64 patients who entered the trial, 60 were eligible, 53 patients were evaluable for toxicity and 47 for efficacy. A total of 169 cycles of carboplatin was given with a median of 2 cycles per patient (range 1-11 cycles) to a median cumulative dose of 798 mg/m(2) (range 290-3879 mg/m(2)). No grade 4 toxicity or toxic deaths occurred. White Blood Cell (WBC) toxicity grade 3 was noted five times, mainly in the radiotherapy pre-treated patients. Grade 3 non-haematological toxicity consisted mainly of nausea and vomiting (21%). There was a total of eight responses (3 Complete Responses (CR) and 5 Partial Responses (PR) with an overall response rate (ORR) of 13% (95% Confidence Interval (CI) 6-25). No responses occurred in patients treated with prior chemotherapy. In evaluable patients, the ORR in all patients (n=47) and in those receiving first-line chemotherapy (n=33) were, 17% (95% CI 8-31) and 24% (95% CI 11-42), respectively. After a median follow-up of 379 days, the median duration of response was 488 days (range 141-5303 days) with two very long responses in patients with a CR. Carboplatin has a low toxicity and is active in chemotherapy-naive advanced endometrial carcinoma patients. These results lead us to propose its use in association in first-line chemotherapy in recurrent or advanced endometrial carcinoma patients. The choice of the initial dose can be determined according to whether the patients have received prior radiotherapy treatment.

"Classical" CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer. An EORTC Breast Cancer Co-operative Group Phase III Trial (10808).

The "classical" CMF (cyclophosphamide/methotrexate/5-fluorouracil) schedule was compared with a modified 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer, as concern had arisen as to whether the classical schedule was the optimal way to give these drugs. The response rate with classical CMF was 48% compared with 29% for intravenous CMF (P = 0.003). Response duration was similar at 11 months, but survival longer for the classical schedule (17 versus 12 months, P = 0.016). We conclude that classical CMF is the superior regimen and attribute this to the higher dose intensity achieved.

An EORTC-IDBBC phase I study of gemcitabine and continuous infusion 5-fluorouracil in patients with metastatic breast cancer resistant to anthracyclines or pre-treated with both anthracyclines and taxanes.

The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and potential activity of combined gemcitabine and continuous infusion 5-fluorouracil (5-FU) in metastatic breast cancer (MBC) patients that are resistant to anthracyclines or have been pretreated with both anthracyclines and taxanes. 15 patients with MBC were studied at three European Organization for Research and Treatment of Cancer centres. 13 patients had received both anthracylines and taxanes. Gemcitabine was given intravenously (i.v.) on days 1 and 8, and 5-FU as a continuous i.v. infusion on days 1 through to 14, both drugs given in a 21-day schedule at four different dose levels. Both were given at doses commonly used for the single agents for the last dose level (dose level 4). One of 6 patients at level 4 (gemcitabine 1200 mg/m2 and 5-FU 250 mg/m2/day) had a DLT, a grade 3 stomatitis and skin toxicity. One DLT, a grade 3 transaminase rise and thrombosis, occurred in a patient at level 2 (gemcitabine 1000 mg/m2 and 5-FU 200 mg/m2/day). Thus, the MTD was not reached. One partial response and four disease stabilisations were observed. Only 1 patient withdrew from the treatment due to toxicity. The MTD was not reached in the phase I study. The combination of gemcitabine and 5-FU is well tolerated at doses up to 1200 mg/m2 given on days 1 and 8 and 250 mg/m2/day given on days 1 through to 14, respectively, every 21 days. The clinical benefit rate (responses plus no change of at least 6 months) was 33% with one partial response, suggesting that MBC patients with prior anthracycline and taxane therapy may derive significant benefit from this combination with minimal toxicity.

Phase II trial for intraperitoneal cisplatin plus intravenous sodium thiosulphate in advanced ovarian carcinoma patients with minimal residual disease after cisplatin-based chemotherapy--a phase II study of the EORTC Gynaecological Cancer Cooperative Group.

On the basis of its efficacy against ovarian carcinoma and its safe peritoneal administration, cisplatin administered by the intraperitoneal route was studied in a phase II multicentric trial. 34 patients with good performance status and residual disease less than 1 cm were treated with a 90 mg/m2 dose (60 mg/m2 at first cycle), administered in the abdominal cavity every 3 weeks for at least four cycles. In case of haematological or renal toxicity, intravenous sodium thiosulphate was perfused simultaneously with intraperitoneal cisplatin with protective intent. 25 patients were evaluable for response: 3 patients had pathological complete response and 1 patient had a microscopic disease (16% response rate in evaluable patients). Systemic toxicity was mild, and sodium thiosulphate clearly protected against leucopenia (6 patients) and renal toxicity (8 patients). Local side-effects were evaluable in 34 patients with 2 cases of infectious peritonitis, 1 of wound infection and 2 of haemorrhage. Of the 147 evaluable chemotherapy cycles, nine resulted in partial and one in total inflow obstruction, for which 4 patients needed surgical procedures for catheter-related complications, and 1 patient died of acute abdominal complications after such a procedure. We conclude that 90 mg/m2 intraperitoneal cisplatin has activity in pretreated patients with minimal residual disease, and that thiosulphate protects against haematological and renal toxicities. Only a randomised study can demonstrate a true benefit, which will have to be balanced with the toxicity of intraperitoneal drug administration.

Continuing chemotherapy or not after the induction treatment in advanced breast cancer patients. clinical outcomes and oncologists' preferences.

The optimal duration of cytostatic treatment for metastatic breast cancer is still a matter of debate. Possible gain in the duration of remission has to be weighed against the side-effects of treatment. Our aim was to define the optimal duration of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) treatment by studying the time to treatment failure, overall survival and using a Q-TWiST analysis. The treating physician's opinion was asked. The European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Group conducted a randomised trial in 204 non-progressing metastatic breast cancer patients after induction chemotherapy (CMF) to stop or continue treatment. Progression-free (PFS) and overall survival (OS) were studied. To gain more insight into the burden of treatment-related side-effects, Q-TWiST was analysed. In addition, we asked for oncologists' preferences as patients are likely to be influenced by their physicians' opinion. Continuation of CMF had a significantly longer time to treatment failure (TTF) 5.2 versus 3.5 months (P=0.011). There was no overall survival (OS) difference 14.0 versus 14.4 months (P=0.77). Mean quality-adjusted survival time was equal to 8.4 months for no further treatment and decreased to 7.9 months for continuation of CMF (95% Confidence Interval (CI) of difference equals 0.5+/-2.5 months). Almost half of the oncologists said they would favour continuous treatment for a 3-month gain in time to progression-a difference which was not found in this study. Based on these data, an interruption of chemotherapy (CMF), if this is the wish of the patient, is justified.

Overexpression of the HER-2 oncogene does not play a role in high-grade osteosarcomas.

The aim of our study was to determine whether or not the tyrosine kinase receptor, HER2 (also known as ErbB2/Her2/neu), is overexpressed in human osteosarcomas (OS). We studied 15 biopsy and 18 resection specimens at the mRNA and protein levels. HER2 status in the OS specimens was assessed by immunohistochemistry (IHC) and quantitative Real-Time Polymerase chain reaction (PCR). In moderately immunopositive cases fluorescent in situ hybridisation (FISH) analysis was used in order to identify any possible gene amplification. 27 samples were evaluable for IHC and only 1 case showed a moderately positive membrane staining. The remaining samples showed no staining or focal cytoplasmic staining (2 samples). In the moderately positive case, FISH analysis showed no HER-2 gene amplification. There was also no overexpression of HER2 mRNA suggesting this sample was a false-positive immunostain. HER2 mRNA expression was present in all samples at a similar level to that in the breast cancer cell line, MCF7, which does not overexpress HER2 and was used as a negative control. In conclusion, this study shows that HER2 mRNA or membranous HER2 protein overexpression is absent in human OS. We noted various inconsistencies in previous published studies, with regard to methodology and the interpretation of the results based on poor methodology. We therefore conclude that the positive data with regard to HER2 overexpression reported in these previous studies is not reliable. Our results suggest that the monoclonal antibody trastuzumab (Herceptin(R)), directed against the HER2-receptor, is not likely to be an effective therapeutic agent in OS.

Promising results with exemestane in the first-line treatment of metastatic breast cancer: a randomized phase II EORTC trial with a tamoxifen control.

Because tamoxifen (TAM), a nonsteroidal antiestrogen, is routinely used in the adjuvant setting, other hormone therapies are needed as alternatives for first-line treatment of metastatic breast cancer (MBC). Currently, exemestane (EXE) and other antiaromatase agents are indicated for use in patients who experience failure of TAM. In this multicenter, randomized, open-label, TAM-controlled (20 mg/day), phase II trial, we examined the activity and tolerability of EXE 25 mg/day for the first-line treatment of MBC in postmenopausal women. Exemestane was well tolerated and demonstrated substantial first-line antitumor activity based on intent-to-treat analysis of peer-reviewed responses. In the EXE arm, values for complete, partial, and objective response, clinical benefit, and time to tumor progression (TTP) exceeded those reported for TAM although no statistical comparison was made. Based on these encouraging results, a phase III trial will compare EXE and TAM.

Stability of patients' preferences for chemotherapy: the impact of experience.

BACKGROUND: Studies have shown that utilities for a particular treatment, elicited by means of a hypothetical treatment scenario, may remain stable within the same patients when examined before, during, and after experiencing that treatment (within-group stability). However, other studies have found that utilities for a particular health state may differ between patient groups who are and who are not experiencing the particular health state (between-group differences). OBJECTIVE: The authors evaluated this apparent contradiction in the case of adjuvant chemotherapy for breast cancer. A related purpose was to examine whether a chemotherapy scenario adequately reflects the patients' own experiences with chemotherapy. METHOD: Forty-three patients with early-stage breast cancer evaluated their actually experienced health state and a chemotherapy scenario before, during, and after undergoing adjuvant chemotherapy (chemotherapy group). A control group of 51 patients for whom chemotherapy was not part of the treatment plan was interviewed at similar points in time. Utilities were elicited by means of a visual analog scale (VAS), a chained time trade-off (TTO), and a chained standard gamble (SG). RESULTS: The utilities for the chemotherapy scenario remained relatively stable over time in the 2 patient groups. Furthermore, the chemotherapy scenario was evaluated more positively by patients in the chemotherapy group than by control patients (e.g., utilities before chemotherapy: VAS 0.69 vs. 0.50, TTO 0.88 vs. 0.50, SG 0.92 vs. 0.58, all Ps < 0.01). Finally, patients in the chemotherapy group evaluated their actually experienced health states during chemotherapy higher than the chemotherapy scenario that was assessed at the same time (VAS 0.79 vs. 0.69, TTO 0.93 vs. 0.87, SG 0.97 vs. 0.96, all Ps < 0.05). CONCLUSIONS: Both within-group stability and between-group differences were found. A possible explanation for within-group stability may be that the chemotherapy scenario did not fully correspond to the patients' actual experiences with chemotherapy ("noncorresponding description"). Therefore, preferences did not change even when the patients' own clinical health status had changed. The between-group differences may be explained by "anticipated adaptation." Both explanations may work together to explain why utilities remain stable within the same patients but differ between different patient groups.

Unstable preferences: a shift in valuation or an effect of the elicitation procedure?

OBJECTIVE: Many studies suggest that impaired health states are valued more positively when experienced than when hypothetical. This study investigated to what extent this discrepancy occurs and examined four possible explanations: non-corresponding description of the hypothetical health state, new understanding due to experience with the health state, valuation shift due to a new status quo, and instability of preference. PATIENTS AND METHODS: Fifty-five breast cancer patients evaluated their actually experienced health state, a radiotherapy scenario, and a chemotherapy control scenario before, during, and after postoperative radiotherapy. Utilities were elicited by means of a visual analog scale (VAS), a chained time tradeoff (TTO), and a chained standard gamble (SG). RESULTS: The discrepancy was found for all methods and was statistically significant for the TTO (predicted utilities: 0.89, actual utilities: 0.92, p < or = 0.05). During radiotherapy, significant differences (p < or = 0.01) were found between the utilities for the radiotherapy scenario and the actual health state by means of the VAS and the SG, suggesting non-corresponding description as an explanation. The utilities of the radiotherapy scenario and the chemotherapy control scenario remained stable over time, and thus new understanding, valuation shift, and instability could be ruled out as explanations. CONCLUSION: Utilities obtained through hypothetical scenarios may not be valid predictors of the value judgments of actually experienced health states. The discrepancy in this study seems to have been due to differences between the situations in question (non-corresponding descriptions).

Phase II study of a combination of cyclophosphamide, adriamycin and cisplatin in advanced fallopian tube carcinoma. An EORTC gynecological cancer group study. European Organization for Research and Treatment of Cancer.

OBJECTIVE: To investigate the clinical activity and toxicity of a combination chemotherapy consisting of cyclophosphamide (C), adriamycin (A) and cisplatin (P) for patients with primary adenocarcinoma of the Fallopian tube having FIGO stage III-IV disease. METHODS: The CAP-regimen consisted of cyclophosphamide 600 mg/m2, adriamycin 45 mg/m2, and cisplatin 50 mg/m2 administered intravenously on day one every 28 days. RESULTS: Twenty-four eligible patients with histologically-confirmed Fallopian tube adenocarcinoma were entered in the trial. Fourteen patients had FIGO stage III, and ten had stage IV disease. The median number of CAP cycles was six. Ten patients had a complete and six had a partial response (response rate: 67%, 95% confidence limits: 45-84%). WHO grade III-IV side-effects included haematological toxicity, nausea/vomiting and alopecia. Furthermore, mild signs of cisplatin-related peripheral neurotoxicity were observed. At a median follow-up of 40 months, nine patients were alive and 15 had died due to malignant disease. The median time to progression was 13 months for all patients. The median overall survival was 24 months and the 1-, 3- and 5-year survival and their 95% confidence limits were 73% (54-92%), 25% (4-46%) and 19% (0-38%), respectively. CONCLUSION: The present data confirm the therapeutic activity of the CAP-regimen in primary Fallopian tube adenocarcinoma. The response rate is moderate and the toxicity profile is acceptable.

[Adjuvant systemic therapy for patients with resectable breast cancer: guideline from the Dutch National Breast Cancer Platform and the Dutch Society for Medical Oncology]. / Adjuvante systemische therapie voor patiënten met resectabel mammacarcinoom; richtlijn van het Nationaal Borstkanker Overleg Nederland en de Nederlandse Vereniging voor Medische Oncologie.

There is an abundance of evidence that adjuvant systemic therapy with chemotherapy or endocrine therapy results in better survival for all patients with resectable breast cancer. The absolute 10-year survival advantage however varies for the different patient groups. Therefore, for each individual patient the choice of adjuvant therapy must take into account the potential benefits and the possible side effects. A group of medical oncologists from the Dutch National Breast Cancer Platform (NABON) and the Dutch Society for Medical Oncology (NVMO) prepared a guideline for the treatment of patients with early resectable breast cancer. The criterium for choosing adjuvant systemic therapy for the individual patient is an expected increase in 10-year survival of 5% or more. In the guideline a difference is made between patients with and without axillary lymph node metastasis. In patients with axillary lymph node metastasis the choice for adjuvant systemic therapy depends on the following prognostic factors: menopausal status, age, and the presence of estrogen and progesterone receptors in the tumour. In patients without axillary lymph node metastasis the choice depends also on the following prognostic factors: the size of the tumour, the mitotic activity index, or the histopathologic grade of differentiation.