Effects of JNJ-40929837, a leukotriene A4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma.

UNLABELLED: Leukotriene B4 (LTB4) is a chemotactic mediator implicated in the pathogenesis of asthma. JNJ-40929837 is an oral inhibitor of LTA4 hydrolase, which catalyzes LTB4 production. We evaluated the effects of JNJ-40929837 in a human bronchial allergen challenge (BAC) model. In this double-blind, 3-period crossover study, 22 patients with mild, atopic asthma were randomized to one of three treatments per period: 100 mg/day JNJ-40929837 for 6 days followed by 50 mg/day on day 7; 10 mg/day montelukast for 6 days; and matched placebo. The BAC was performed on day 6 of each treatment period. Primary outcome was BAC-induced late asthmatic response (LAR) measured by maximal percent reduction in forced expiratory volume (FEV1) in one second. Secondary outcomes included early asthmatic response (EAR) by maximal percent reduction in FEV1, EAR and LAR evaluated by area under the FEV1/time curve (AUC0-2, AUC3-10, respectively), change in baseline FEV1 after 5-day treatment, safety, and correlation of JNJ-40929837 to the divalent cation ionophore A23187-stimulated whole blood LTB4 levels and sputum basal LTB4 levels. No significant differences were observed in the primary or secondary FEV1 endpoints with JNJ-40929837 versus placebo. Compared with placebo (n = 17, LS mean = 27.7), there was no significant attenuation of the maximal percent reduction in the LAR FEV1 with JNJ-40929837 (n = 16, LS mean = 28.6, P = 0.63) but montelukast (n = 17, LS mean = 22.6, P = 0.01) significantly attenuated the LAR. JNJ-40929837 substantially inhibited LTB4 production in whole blood, decreased sputum LTB4 levels and was well-tolerated. The number of adverse events leading to study withdrawal was the same in JNJ-40929837 and placebo groups. In conclusion, JNJ-40929837 demonstrated target engagement in blood and sputum. No significant impact in response to allergen inhalation was observed with JNJ-40929837 versus placebo. REGISTRATION: This study is registered at ClinicalTrials.gov: NCT01241422.

Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results.

BACKGROUND: A randomized trial conducted by the Gynecologic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new "standard," a group of European and Canadian investigators planned a confirmatory phase III trial. METHODS: This intergroup trial recruited 680 patients with broader selection criteria than the GOG #111 study and administered paclitaxel as a 3-hour instead of a 24-hour infusion; progression-free survival was the primary end point. Patient survival was analyzed by use of the Kaplan-Meier technique. Treatment effects on patient survival were estimated by Cox proportional hazards regression models. All statistical tests were two-sided. RESULTS: The overall clinical response rate was 59% in the paclitaxel group and 45% in the cyclophosphamide group; the complete clinical remission rates were 41% and 27%, respectively; both differences were statistically significant (P =.01 for both). At a median follow-up of 38.5 months and despite a high rate of crossover (48%) from the cyclophosphamide arm to the paclitaxel arm at first detection of progression of disease, a longer progression-free survival (log-rank P =.0005; median of 15.5 months versus 11.5 months) and a longer overall survival (log-rank P =. 0016; median of 35.6 months versus 25.8 months) were seen in the paclitaxel regimen compared with the cyclophosphamide regimen. CONCLUSIONS: There is strong and confirmatory evidence from two large randomized phase III trials to support paclitaxel-cisplatin as the new standard regimen for treatment of patients with advanced ovarian cancer.

Stage Ib cervical cancer during pregnancy: planned delay in treatment--case report.

Approximately 0.05% of pregnancies are complicated with cervical cancer. Treatment of this malignancy during pregnancy depends on the stage of disease and gestational age at the time of diagnosis. In women with Stage IB cervical cancer immediate treatment, without regard to the pregnancy, is traditionally advocated in the first and second trimester. A planned delay of treatment, to achieve foetal maturity, may be acceptable if there are no adverse maternal and foetal consequences. We present a case of a Stage IB1 cervical cancer, diagnosed during a twin pregnancy, and treated with a planned delay of 19 weeks. We have reviewed the literature and focused on what is known about planned delay in therapy of Stage IB cervical cancer, diagnosed before 30 weeks of gestational age.

Dose-effect study of carboplatin in ovarian cancer: a Danish Ovarian Cancer Group study.

PURPOSE: To elucidate the effect of a doubled carboplatin dose-intensity in epithelial ovarian cancer in combination with a fixed dose of cyclophosphamide. PATIENTS AND METHODS: A total of 222 patients with epithelial ovarian cancer stages II to IV were included in the study. Following surgery, patients were randomly assigned to receive carboplatin at an area under the concentration-versus-time curve (AUC) of 4 (AUC4) or carboplatin at an AUC of 8 (AUC8) and cyclophosphamide 500 mg/m2 given every 4 weeks for six courses. The AUC was calculated according to Calvert's formula. In 123 patients, the carboplatin AUC was also measured based on a single-sample method and the results were compared with the calculated AUC. The end points of the trial were complete pathologic remission (CPR) and crude survival. RESULTS: Approximately 50% of patients in both arms underwent second-look surgery. The frequency of CPR was 32% and 30%, respectively. The survival curves showed no significant difference (P = .84). The dose-intensity of cyclophosphamide was almost identical in the two arms, whereas that of carboplatin was different. In the AUC8 arm, the dose-intensity was 1.86 times that of the AUC4 arm. The results also demonstrated good agreement between the calculated and the measured AUC in most patients. Bone marrow toxicity was significantly higher in the AUC8 arm. CONCLUSION: A doubling of the carboplatin dose-intensity did not result in any significant improvement of pathologic remission or survival. Calvert's formula can be used to give a fairly accurate estimate of the carboplatin AUC. Bone marrow toxicity increased with higher dose-intensity, and a further increase of dose is only feasible with growth-factor or stem-cell support.

Blood transfusion and prognosis in Dukes' B and C colorectal cancer.

To evaluate the prognostic influence of blood transfusion in cancer patients, transfusion data were reviewed on 468 radically operated patients (260 Dukes' B and 208 Dukes' C) with carcinoma of the rectum and the rectosigmoid. Data on whole blood and packed red blood cell transfusions were recorded together with a number of clinical, pathological and histochemical characteristics. The endpoint used was death with cancer. All patients were followed for 2-7 years or until time of death. Univariate statistical methods revealed a highly significant trend towards worsened prognosis with increasing volume of transfusion blood. However, this effect was insignificant when multivariate statistical methods were employed: patients receiving whole blood or packed red blood cell transfusions did no worse than expected from their clinico-pathological characteristics. It is concluded that in this series the observed association between transfusion status and prognosis is adequately explained by a multivariate prognostic model including well-established prognostic factors.

Misonidazole combined with radiotherapy in the treatment of carcinoma of the uterine cervix.

Between April 1979 and January 1982, 331 patients were included in a study to establish whether misonidazole (MISO) had any effect as an adjuvant to radiotherapy in the treatment of squamous cell carcinoma of the uterine cervix (FIGO Stage IIb, III, and IVa). Patients were randomized to receive either MISO (12 g/m2 applied within 6 weeks) or placebo. This was given in conjunction with each institution's normal radiotherapy schedule and thus varied with regard to external and intracavitary irradiation. The analysis was performed based on patients' status at January 1986, with all patients observed for at least 4 years. One hundred and sixty-four patients received MISO and 167 placebo. Compliance to radiotherapy was good and MISO was well tolerated. The overall rates for MISO vs. placebo were as follows: local tumour control, 50 vs. 54%; disease-free survival, 47 vs. 46%, and crude survival, 39 vs. 45%. A similar lack of MISO effect was found in the individual stages. However, patients in all stages with hemoglobin concentrations below 7 mmol/l had a significantly lower local control probability (overall 24 vs. 47%), whereas the incidence of distant metastases was unaffected. We conclude that the addition of MISO did not influence the radiation response in advanced uterine carcinoma. The reasons for this ineffectiveness are yet to be clarified.

Major or local surgery for cure in early rectal and sigmoid carcinoma--a prospective evaluation.

The results of different types of treatment for early cancer in 158 out of 1,300 patients with rectal and sigmoid cancer were evaluated in a prospective study from 1979 to 1984. Radical surgery was performed in 121 patients (mean age 66 years) with cancer Dukes' A (median diameter 3 cm), while 37 patients (mean age 71) with smaller cancers (median 2 cm) had polypectomy or local excision. Post-operative complications were significantly more frequent in the first group. No patients in any of the two groups with carcinoma in pedunculated adenomas or within the upper half of the submucosa or above 9 cm from the anal verge had recurrent cancer. CEA-measurements had no prognostic value. No difference was found in crude or cancer-related death between the two groups. The overall results support the use of local treatment in elderly patients with complicating disease, having small cancers, not penetrating the tunica muscularis externa of the rectosigmoid wall.

What have we achieved in ovarian cancer? A comparison of survivals and resources in two different periods.

In a geographically well-defined region in Denmark, survival and resource spending for strictly defined epithelial ovarian cancer patients treated during the periods 1973-1978 and 1981-1986 were compared. Almost all epithelial ovarian cancer patients diagnosed during the periods involved were identified; in both periods 206 patients were found. The number of patients was cross-checked with the Danish Cancer Registry. Treatment strategy was totally different in the two periods. In the first period debulking surgery was not routine and postoperative treatment consisted of pelvic irradiation and alkylating agents. In the second period the patients were treated according to national protocols prescribing debulking surgery, second-look laparotomy, and allocation to randomized trials. Advanced ovarian cancer patients were treated with combination chemotherapy with cisplatinum. Median survival was superior for the period 1981-1986, but long-term survival was similar in the two periods, 5-year survival being 27.5% for the period 1973-1978 and 26.9% for the period 1981-1986. The resources spent on ovarian cancer patients were calculated for the two periods, expressed as 'bed-days' spent on ovarian cancer. An estimate of the price of the extra resources used was made; in the second period $1.18 million $US more were spent on ovarian cancer. The costs were correlated with survival and the cost per gained year of life was estimated as $36 493. In conclusion, the study shows that for all stages of ovarian cancer an improvement of median survival was found, but not of long-term survival. The survival gain was associated with extra resource spending.

Long-term survival and prognostic factors in advanced epithelial ovarian cancer with special emphasis upon the effects of protocol inclusion.

The Danish Ovarian Cancer Study Group registered 722 patients in stages III and IV during the period 1981-1986. The material included 85% of all ovarian cancer patients in the catchment area of the group and patients allocated to protocol as well as patients treated outside protocols. Five and 10-year survival were: stage III 17%, and 8%, respectively; and stage IV 4% and 2%. Patients allocated to protocol had a significantly better survival than patients not included in protocols even when only patients younger than 70 years were compared. All non-protocol patients had a poorer prognosis irrespective of the reason for exclusion. Five-year survival for stage III protocol patients was 25% vs. 9%, for non-protocol patients younger than 70 years. The 10-year survival was 11% and 4% for stage III protocol and non-protocol patients, respectively. A multivariate analysis showed that residual tumor, age, stage, and performance status had prognostic value. In non protocol patients histologic grade had an additional marginal prognostic impact. In conclusion the study showed that the statement that long-term survival in advanced ovarian cancer has been increased could not be proven by comparison of survival from randomized studies performed in the early eighties with survival of stage III and IV patients before the introduction of cisplatinum chemotherapy. It is necessary to consider survival of all patients, protocol and non-protocol in a geographically well-defined region for evaluation of survival improvement.

Reproducibility and prognostic value of histologic type and grade in early epithelial ovarian cancer.

From September 1981 to September 1986, 417 consecutive treated patients with epithelial ovarian cancer FIGO stage I and II were registered by the Danish Ovarian Cancer Group (DACOVA). Typing and grading were primarily performed by several pathologists, with and without training in gynecologic pathology. Review typing by one specially trained pathologist showed an agreement rate of 72% for serous and endometrioid carcinoma, 86% for mucinous and 100% for clear cell carcinoma. The agreement rate was calculated for patients primarily classified by pathologists trained in gynecologic pathology and for patients primarily classified by pathologists with and without training. The agreement rate was not better for the group of pathologists with special training in gynecologic pathology. Grading was performed according to two classifications: one based on architectural pattern and one on combined criteria. Review grading showed an agreement rate of 77% for architectural classification and an agreement rate of 52% for combined classification. The agreement rate between the two grade classifications at review was only 62%. Combined grading showed a significant tendency towards classifying more tumors as low grade. All grade classifications had prognostic value. The poor agreement rate of both type and grade even when performed by pathologists with expertise in gynecologic pathology, calls for a better and more reproducible characterization of malignant ovarian tumors.

Prognostic factors and adjuvant treatment in early epithelial ovarian cancer.

Four hundred and ten patients with epithelial ovarian cancer FIGO stages I and II were registered by a Danish multicenter study group (The Danish Ovarian Cancer Group - DACOVA). Two-thirds were stage I, the most frequent substage was Iai which was the classification in 27%. Five-year survival for stage I was 72%, and 38% for stage II. Multivariate analysis showed that age, stage, residual tumor, histologic grade and adjuvant treatment had prognostic value. For stage, three significantly different groups could be identified: (1) stage Iai, (2) stage Iaii-Ic, and (3) stage II. Histologic grade showed a significant survival difference between all grades. Adjuvant treatment had a moderate but significant impact on survival. Patients in stage Iai had a good survival with surgery alone and will probably not benefit from adjuvant therapy. Adjuvant treatment improved survival for the remaining patients in stages I and II without residual tumor. A difference between treatment modalities was not observed. However, the data need to be confirmed by a randomized trial. Patients in stage II with residual tumor should be treated as stage III.

[Was chemotherapy beneficial for the patients with advanced ovarian cancer? A comparison of survival and resource use in two different time periods]. / Har kemoterapi gavnet patienter med avanceret ovariecancer? En sammenligning of overlevelse og ressourceforbrug i to forskellige tidsperioder.

Around 1980, aggressive surgery and combination-chemotherapy were introduced as routine therapy in advanced ovarian cancer. It is interesting to evaluate whether this has been associated with an improvement of survival. A comparison between patients diagnosed in the county of Funen during the period April 1973 to April 1978 with patients diagnosed during the period September 1981 to September 1986 was made. In the last period the patients were treated according to the DACOVA guidelines (Damish Cancer of the Ovaries). An improvement in median survival but not in five-year survival was registered. The number of hospital bed-days during the two periods was calculated. In the second period the number of hospital bed-days was seven days higher per patient than in the first period. The cost per gained year of life was 240,000 Dkr. in 1992 prices.

[Treatment of cervix cancer in Denmark]. / Behandlingen af cancer cervicis uteri i Danmark.

The current status of cervical cancer treatment in Denmark is discussed. Diagnostic aspects and problems of classification are presented briefly supplemented with a comment on new prognostic parameters based on a semiquantitative score system and flow cytometry. Surgery is the treatment of election for the early stages whereas radiotherapy is the treatment of choice in advanced stages. Chemotherapy should only be employed in the framework of clinical trials. It is concluded that centralised treatment should be maintained.

[Prognosis in synchronous liver metastasis from colorectal cancer. A multicenter study of patients with cancer of the rectum and cancer of the rectosigmoid colon]. / Prognosen ved synkrone levermetastaser fra kolorektal cancer. En multicenterundersgelse af patienter med cancer recti et rectosigmoidei.

A prospective investigation of 188 patients with cancer of the rectum and rectosigmoid colon with synchronous liver metastases is described. The mean survival time for 183 patients who did not receive any treatment for the liver metastases was six months and only one survived for longer than 37 months. After extirpation of the primary tumour, the most significant prognostic factors were etrahepatic metastases, enlarged liver on account of metastases and more than three liver metastases. Serum basic phosphatases had the greatest significance among a series of laboratory tests. In the sub-groups with the best possible prognoses, the mean survival time was 12 months. 25% five-year survival has been described in the literature following resection of the liver in patients with a maximum of three metastases, no other metastases and age under 70 years. Provided this holds true, liver surgery will be a therapeutic possibility in at least 100 patients per annum in Denmark with synchronous liver metastases and 25 of these will be cured. This figure requires an improved programme for the diagnosis of synchronous liver metastases than at present and the same high frequency of extirpation of the primary colorectal cancer on a national basis which was achieved in the present material.

[Patients with early stages of endometrial cancer should be spared adjuvant radiotherapy. Danish Endometrial Cancer Group]. / Patienter med tidlige stadier af endometriecancer bør skånes for adjuverende strålebehandling.

In an attempt to create uniform nationwide guidelines for the management of all stages of endometrial carcinoma, and to limit the use of adjuvant radiation therapy in stage I disease to high-risk patients only, a protocol was developed by the Danish Endometrial Cancer group (DEMCA). From September 1986 through August 1988, 1214 women in Denmark with newly diagnosed carcinoma of the endometrium have been treated according to this protocol. This figure represents all endometrial carcinomas diagnosed in Denmark during this two-year period. The primary treatment was total abdominal hysterectomy and bilateral salpingo-oophorectomy, no preoperative radiation therapy was delivered. In 1039 cases no macroscopic residual tumour and/or microscopic tumor tissue in the resection margins was found following surgery. Based on surgery and histopathology, these patients were classified as: P-stage I low risk (n = 641), P-stage I high risk (n = 235), P-stage II (n = 105) and P-stage III, Group 1 (n = 58). No postoperative radiation therapy was given to P-I low risk cases. P-I high risk, P-II, and P-III (Group 1) cases received external radiation therapy. Recurrence rate at 68-92 months follow-up was 45/641 (7%) in P-I low risk, 36/235 (15%) in P-I high risk, 30/105 (29%) in P-II, and 27/58 (47%) in P-III (Group 1) cases. Fifteen of 17 vaginal recurrences in P-I low risk cases were salvaged (mean observation time 61 months). In this population-based investigation it has been shown that P-stage low-risk patients are adequately treated by total abdominal hysterectomy and bilateral salpingo-oophorectomy, and that no pre- or postoperative radiation therapy is necessary.