Long-term toxic effects of adjuvant chemotherapy in breast cancer.

Breast cancer is the most common malignant tumor affecting women. Adjuvant systemic therapies have been shown to have a significant impact on reducing the risk for breast cancer recurrence and overall mortality. Chemotherapy remains an important and frequently used treatment option in the adjuvant setting, and the associated short-term adverse events are very well described. However, there is insufficient information regarding the long-term sequelae of most chemotherapeutic agents. In this review, we describe different potential long-term adverse events associated with adjuvant chemotherapy in breast cancer, with a particular focus on long-term cardiac toxicity, secondary leukemia, cognitive function, and neurotoxicity. In addition, we discuss the effect of adjuvant chemotherapy on fertility and sexual function of young breast cancer patients. These adverse events are frequently overshadowed by the well-demonstrated clinical efficacy and/or reassuring short-term safety profiles of the different chemotherapy regimens commonly used today. We believe that a proper understanding and appreciation of these adverse events will enable us to refine our strategies for managing breast cancer. The fact that adjuvant chemotherapy is often given to patients who might not really need it urges us to consider the whole spectrum of chemotherapy risks versus benefits to maximize benefit without compromising quality of life.

EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry: correlation with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab.

BACKGROUND: In an attempt to identify markers of resistance to trastuzumab, we evaluated both the profiling of human epidermal growth factor receptor 2 (HER2)-positive tumor cells measuring the relative levels of EGFR, pMAPK, pAkt and PTEN and their correlations with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab. PATIENTS AND METHODS: Tumor tissues for this retrospective analysis were available from 45 out of 76 patients with metastatic breast cancer treated from April 1999 to March 2006 with trastuzumab-based therapy at our Institution. Evaluations of EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry (IHC) were carried out on all 45 tissue samples and their correlations with response to trastuzumab, incidence of central nervous system (CNS) metastases, time to progression (TTP), overall survival from diagnosis of breast cancer (OS1), from diagnosis of metastatic disease (OS2) and from the start of trastuzumab (OS3) were analyzed. RESULTS: We observed that TTP (P = 0.001) and median OS2 and OS3 were significantly longer in patients responsive to trastuzumab-based regimen compared with nonresponsive patients. EGFR, pMAPK, pAkt and PTEN status by IHC were not significantly associated with response to trastuzumab, TTP, overall survival (OS1, OS2, OS3) and CNS metastases incidence. A trend for shorter OS3 was observed for pMAPK-positive patients compared with pMAPK-negative patients (22.8 versus 31.2 months; P = 0.076). Median OS1 resulted shorter in 22 pAkt-positive patients (69.8 months) compared with 23 pAkt-negative patients (108.2 months); P = 0.091. It is likely that high expression of pMAPK (pMAPK-positive status) or pAkt (pAkt-positive status) could identify a subgroup of HER2-positive tumors with high activity of proliferation and survival pathways and with resistance to trastuzumab. CONCLUSIONS: In HER2-positive metastatic breast cancers, EGFR, pMAPK, pAkt and PTEN status evaluated by IHC was not significantly associated with response to trastuzumab, TTP, OS and CNS metastases incidence. However, HER2 status determined by IHC and/or FISH assays may not be sufficient to predict response to trastuzumab-based therapy.

Aromatase inhibitors: a new reality for the adjuvant endocrine treatment of early-stage breast cancer in postmenopausal women.

Tamoxifen, a selective estrogen receptor modulator (SERM), has been used for many decades as the "gold standard" adjuvant treatment for patients with hormone-receptor-positive early breast cancer. This drug, when administered for 5 years, reduces the risk for recurrence, contralateral breast cancer (BC) and death. The optimal duration of tamoxifen in the adjuvant setting has not been established yet, but it has been demonstrated that 5 years are better than shorter treatment while it is still unclear if a prolongation of the treatment for more than 5 years is worthwhile. In the last few years, third generation aromatase inhibitors (AIs), either steroidal (exemestane) or non-steroidal (anastrozole, letrozole), have shown to be an effective alternative to tamoxifen in postmenopausal patients with BC regardless of its stage. These agents act by blocking the aromatase enzyme which converts androgens into estrogens. The goal of this article was to review the results of recent randomized trials comparing AIs to tamoxifen in postmenopausal women in the adjuvant setting. Two strategies have been utilized: a direct upfront comparison in which both tamoxifen and AIs were given for 5 years or an early switch in which AIs were administered after 2-3 years of tamoxifen for 3-2 years or vice versa. Both strategies have shown a superiority of AIs over tamoxifen and a different safety profile but, the optimal treatment modality has yet to be defined. Moreover, in an attempt to further reduce patients' risk of recurrence after the administration of tamoxifen for 5 years, three trials have evaluated the role of prolonging the adjuvant treatment with AIs for 5 more years in comparison to placebo (late switch). A significant improvement of disease-free survival and of overall survival in the subgroup of node-positive patients, at least in one trial, has been observed with AIs. Despite these important results several unanswered questions remain and the results of ongoing trials will hopefully clarify some of them.

CagA and VacA Helicobacter pylori antibodies in gastric cancer.

BACKGROUND: Infection with different genotypes of virulent Helicobacter pylori strains (cytotoxin-associated gene A [CagA]- and/or vacuolating cytotoxin A [VacA]-positive) can play a role in the development of atrophic gastritis, duodenal ulcer (DU) and gastric cancer (GC). OBJECTIVE: To determine whether patients with GC and H pylori-negative histological staining had previously been infected with H pylori CagA- and/or VacA-positive virulent strains. METHODS: Twenty-three GC patients with a mean (+/- SD) age of 68.14+/-9.8 years who tested H pylori-negative on histological staining took part in the study. Three control groups were included. The first group comprised 19 patients with past H pylori infection and DUs eradicated 10 years earlier, with a mean age of 58+/-18.2 years. H pylori-negative status for this group was determined every year with Giemsa staining, and follow-up testing occured 120+/-32 months (mean +/- SD) after therapy. The subsequent control groups included 20 asymptomatic children, with a mean age of 7+/-4.47 years, and with H pylori-negative fecal tests; the final group contained 30 patients without clinical symptoms of H pylori infection, with a mean age of 68+/-11.6 years, who tested H pylori-negative by histological staining. RESULTS: Prevalence of CagA and VacA seropositivity, respectively was 82.6% and 73.91% in GC patients; 84.2% and 84.2% in H pylori-negative DU patients; 25% and 5% in H pylori-negative children; and 36.6% and 16.6% in the patients without clinical symptoms on histological staining. CagA and VacA antibody positivity was not significantly different between GC patients and patients with DUs that had been eradicated 10 years earlier. Significant positivity was found between the children's group and the H pylori-negative (with past DUs) group (P<0.001). A statistically significant difference was found in age between groups (P<0.03). CONCLUSIONS: Patients with GC, even when H pylori-negative at the time of the present study, may have been infected by H pylori before the onset of the disease, as confirmed by CagA and VacA seropositivity. These data reinforce the hypothesis that H pylori may be a direct carcinogenic agent of GC.

Evaluation of serum HER2 extracellular domain in early breast cancer patients: correlation with clinicopathological parameters and survival.

BACKGROUND: We explored the correlation between serum human epidermal growth factor receptor-2 (HER2) extracellular domain (ECD) and tissue HER2 status, their relationship with clinicopathological parameters and their impact on disease-free survival (DFS) and overall survival in early breast cancer patients. PATIENTS AND METHODS: This prospective trial included patients with stage I-III breast cancer. Serum HER2 ECD levels were measured by two enzyme-linked immunosorbent assays before surgical treatment. Tissue HER2 status was analyzed by immunohistochemistry (IHC) in all tumors; FISH assay was utilized in HER2 2+ tumors by IHC. RESULTS: From May 2000 to July 2005, 256 consecutive stage I-III breast cancer patients were included in this study. High serum HER2 ECD levels (>or=15 ng/ml) were reported in 23 patients (9.0%) and HER2-positive status in tumor tissue was observed in 42 patients (16.4%) with a concordance of 87.1%. High HER2 ECD levels were significantly associated with high histological grade (P = 0.003), stage III (P = 0.008), lymph node involvement (P = 0.035) and negativity of both estrogen (P = 0.016) and progesterone (P = 0.007) receptors. At multivariate analysis, high serum HER2 ECD levels were a significant independent prognostic factor of worse DFS (P = 0.009). CONCLUSIONS: A statistically significant association was observed between high serum HER2 ECD levels and worse DFS in early breast cancer patients.

HER-2 overexpression/amplification and its interaction with taxane-based therapy in breast cancer.

Breast cancer (BC) is the most common cancer in women and it is incurable when metastases are diagnosed. Taxanes, namely docetaxel and paclitaxel, are effective chemotherapeutic agents in the metastatic, neoadjuvant and adjuvant settings. HER-2 overexpression/amplification is detected in 25-30% of BCs and confers aggressive tumor behavior as well as resistance to some systemic treatments; nevertheless, its association with response to taxane-based chemotherapy is still unclear, with conflicting results in both in vitro and in vivo preclinical studies. This review will address the impact of HER-2 overexpression/amplification in BC patients treated with taxanes. Prospective, randomized trials incorporating important biological hypotheses are either ongoing or just closed, and their results will hopefully help to shed more light on this issue.

Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients.

The Ki-67 antigen is used to evaluate the proliferative activity of breast cancer (BC); however, Ki-67's role as a prognostic marker in BC is still undefined. In order to better define the prognostic value of Ki-67/MIB-1, we performed a meta-analysis of studies that evaluated the impact of Ki-67/MIB-1 on disease-free survival (DFS) and/or on overall survival (OS) in early BC. Sixty-eight studies were identified and 46 studies including 12 155 patients were evaluable for our meta-analysis; 38 studies were evaluable for the aggregation of results for DFS, and 35 studies for OS. Patients were considered to present positive tumours for the expression of Ki-67/MIB-1 according to the cut-off points defined by the authors. Ki-67/MIB-1 positivity is associated with higher probability of relapse in all patients (HR=1.93 (95% confidence interval (CI): 1.74-2.14); P<0.001), in node-negative patients (HR=2.31 (95% CI: 1.83-2.92); P<0.001) and in node-positive patients (HR=1.59 (95% CI: 1.35-1.87); P<0.001). Furthermore, Ki-67/MIB-1 positivity is associated with worse survival in all patients (HR=1.95 (95% CI: 1.70-2.24; P<0.001)), node-negative patients (HR=2.54 (95% CI: 1.65-3.91); P<0.001) and node-positive patients (HR=2.33 (95% CI: 1.83-2.95); P<0.001). Our meta-analysis suggests that Ki-67/MIB-1 positivity confers a higher risk of relapse and a worse survival in patients with early BC.

Adjuvant chemotherapy in 2005: standards and beyond.

The 2003 St. Gallen consensus panel divided the many available adjuvant chemotherapy (CT) regimens into those with "standard efficacy" (ACx4, CMFx6) and those with "superior efficacy" (FA(E)Cx6, CA(E)Fx6, A(E)-->CMF, TACx6, ACx4--> paclitaxel (P)x4 or docetaxel (D)x4) but also greater complexity, toxicity and cost. This paper will summarize the latest information on long-term side effects of the "superior" regimens and 5-year benefits reported in taxane trials, including those of a "new" sequential regimen, FECx3--> docetaxelx3. Rapidly expanding evidence of marked heterogeneity in the magnitude of CT benefits according to the tumour oestrogen receptor (ER) status, a claim made for many years by IBCSG investigators, will be reviewed; it will lead to the conclusion that a revolution needs to take place in the way oncologists think about the CT added value and design adjuvant clinical trials. The conclusions proposed to the 2005 St. Gallen consensus panel are that: adequately dosed anthracycline-based CT regimens remain an acceptable standard for many women; a lower threshold for using taxanes in sequence or combination with anthracyclines (A) is justified in the presence of an ER-negative or low-ER tumour status, other aggressive biologic features (such as HER-2 overexpression), fear about A-induced cardiotoxicity; no recommendation can yet be made as far as the optimal taxane-A regimen, the best taxane or the best taxane schedule.

Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now?

In the last few decades, proliferative markers have been broadly evaluated as prognostic and predictive factors for early stage breast cancer patients. Several papers evaluating one or more markers have been published, often with contradictory results. As a consequence, there is still uncertainty about the role of these proliferative markers. The present paper critically reviews the current knowledge about the following markers: thymidine labeling index, S phase fraction/flow cytometry, Ki 67, thymidine kinase (TK), cyclins E, cyclin D, the cyclin inhibitors p27 and p21, and topoisomerase IIalpha. For each marker, the prognostic and predictive role was separately analyzed. Only papers published in English in peer-reviewed journals before June 2004 that include at least 100 evaluable patients were selected. In addition, the prognostic and predictive role of the proliferative markers had to be assessed through multivariate analyses. One hundred and thirty-two papers fulfilled these criteria and 159 516 patients were analyzed. Unfortunately, several methodological problems in the research to date prevent us from including any one of these proliferative markers among the standard prognostic and predictive factors. Early incorporation of translational research and new technologies with clinical trials are needed to prospectively validate biological markers and allow their use in clinical practice.

Use of IgG Avidity test in case definitions of toxoplasmosis in pregnancy.

A survey network for congenital toxoplasmosis (TOXO-NET) was set up in December 1996 in Piedmont (Italy). Participants were asked to classify the infections in pregnant mothers and newborns by the criteria of the European Network on Congenital Toxoplasmosis published by Lebech in 1996. Because the IgG Avidity test is largely employed as a 2nd level test in toxoplasmosis diagnosis and it could be helpful to date infection, the co-ordinators of TOXO-NET suggested including it in the "case definition" of "probable" infection and "unlikely" infection. 117 cases of toxoplasmosis in pregnancy divided into the risk categories under Lebech's criteria were re-examined using the "new" case definitions. 77 out of 117 (65.8%) Toxoplasma gondii infections during pregnancy could be defined with only one serum sample using the IgG Avidity test. The IgG Avidity test proved a useful method to classify the Toxoplasma gondii infections in pregnancy, especially when we had only one serum sample.

Phase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer.

Synergism between anti-HER2 monoclonal antibody (trastuzumab) and paclitaxel has been shown in vitro and in vivo. In previous experiences, weekly administration of trastuzumab and paclitaxel has shown significant activity in metastatic breast cancer. In this phase II study, we evaluated the activity and the toxicity of this weekly regimen in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer. Between November 1999 and July 2001, 25 patients were treated with trastuzumab (4 mg kg(-1) i.v. loading dose followed by 2 mg kg(-1) i.v. week(-1)) and paclitaxel (60-90 mg m(-2) h(-1) i.v. infusion week(-1)). The treatment was planned to continue until disease progression or prohibitive toxicity; in patients with responsive or stable disease, after 6 months of therapy, the decision to stop paclitaxel while continuing weekly trastuzumab was left to the physicians' judgement. At the median follow-up of 19.6 months (range 9.2-38.1), all patients are evaluable for response and toxicity. We obtained four (16%) complete responses (CR), 10 (40%) partial responses (PR), four (16%) stable diseases and seven (28%) disease progressions. The response rate (CR+PR) was 56% (95% CI, 36.5-75.5%). The median duration of response was 10.4 months (range 4.1-24.2+). Median time to progression was 8.6 months (range 2.5-24.2+). The toxicity was mild; five patients experienced fever and chills during the first infusion of trastuzumab (20%); leukopenia grade 2 was recorded in one patient (4%). Two patients (8%) came off study for grade 3 cardiotoxicity (after 9 and 17 weeks of treatment, respectively): both had already received anthracyclines and taxanes. Onycholysis grade 2 was observed in five patients (20%). These results confirm that weekly administration of trastuzumab and paclitaxel is active in anthracycline- and taxane-pretreated metastatic breast cancer patients HER2-overexpressing. Since cardiac disfunctions grade 3 were observed (8%), we recommend that cardiac function should be monitored in these patients.

Evaluation of the prognostic role of vascular endothelial growth factor and microvessel density in stages I and II breast cancer patients.

In this study, we retrospectively evaluated the expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in 228 and 213 specimens, respectively, from stages I and II breast cancer patients (pts) enrolled in a randomized phase III adjuvant chemotherapy trial comparing epirubicin to CMF, while tamoxifen was given to all postmenopausal pts. The expression of VEGF and MVD was assessed on tissue sections formalin-fixed and paraffin-embedded by immunohistochemical staining using anti-VEGF antibody of human origin and anti-CD34 monoclonal antibody. Univariate and multivariate analysis were performed using chi squared test, log-rank test and Cox's regression model. Sixty four of 228 pts were classified as VEGF positive (28%) with no significant difference in the two treatment arms. In 213 pts evaluated for CD34, 103 pts (48%) were classified as MVD high. No significant association between VEGF and MVD was found, and neither were they correlated with many known prognostic factors such as age, tumor size, nodal status, and histological grade. The only significant correlations observed were between VEGF and estrogen receptor (ER) status (p = 0.013) and between MVD and HER2 overexpression (p = 0.023). At a median follow up of 96 months VEGF and MVD were not correlated with relapse-free survival (RFS) and overall survival (OS) in all pts and in pts assigned to one of the two treatment arms. In conclusion, VEGF and MVD retrospectively evaluated, cannot be considered prognostic factors in node negative (N-) high risk and node positive (N+) breast cancer pts treated with two different regimens of adjuvant chemotherapy.

Epirubicin versus CMF as adjuvant therapy for stage I and II breast cancer: a prospective randomised study.

We compared a relatively short regimen of monochemotherapy with epirubicin versus polychemotherapy with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) as adjuvant treatment for stage I and II breast cancer patients. 348 patients with oestrogen receptor negative (ER-) node negative and ER- or ER+ node-positive with <10 nodes were accrued. CMF was given intravenously (i.v.) on days 1 and 8, every 4 weeks, for six courses; epirubicin was given weekly for 4 months. Postmenopausal patients received tamoxifen for 3 years. The primary endpoints were overall survival (OS), relapse-free survival (RFS) and event-free survival (EFS). Outcome evaluation was performed both in eligible patients and in all randomised patients according to the intention-to-treat principle. 8 randomised patients were considered ineligible. At a median follow-up of 8 years, there was no difference in OS (Hazard Ratio (HR)=1.11, 95% Confidence Interval (CI): 0.77-1.61, P=0.58), EFS (HR=1.14, 95% CI: 0.78-1.64, P=0.48), and RFS (HR=1.14, 95% CI: 0.8-1.64, P=0.48) between the two arms for all of the patients. At 8 years, the RFS percentages (+/-Standard Error (S.E.)) were 65.4% (+/-4%) in the CMF arm and 62.7% (+/-4%) in the epirubicin arm; for EFS these were 64.2% (+/-4%) for CMF and 60.8% (+/-4%) for epirubicin, respectively. A significant difference in RFS (P=0.015) was observed in patients with 4-9 positive nodes in favour of the CMF arm. Toxicity in the two arms was superimposable except for more frequent grade 3 alopecia in the epirubicin-treated patients (P=0.001). Overall, at a median follow-up of 8 years, there were no differences between the two arms in terms of OS, EFS and RFS.

Helicobacter pylori antibodies (CagA and VacA) detection. The link between cancer and infection.

BACKGROUND: Infection with different genotypes of virulent Helicobacter pylori (Hp) strain, CagA and/or VacA positive, can play a role in the development of atrophic gastritis, duodenal ulcer (DU), and gastric carcinomas (GC). This study was undertaken to investigate if patients with GC with Hp negative histological Giemsa staining had a past infection by virulent strains of Hp CagA and/or VacA positive. METHODS: Twenty GC, (average age +/- SD) 68.14+/-9.8 years old, Hp negative to histological take part to the study. Two-control group were included: 19 Hp infected patients with DU eradicated 10 years before, 58+/-18.2 yrs. Hp negative status was determined every year with histology and follow-up after therapy was 120+/-32 months; range 96-144 months. Twenty asymptomatic children, 7+/-4.47 yrs, with Hp negative faecal test. The immunoblot assay was used to detect serum antibodies against CagA and VacA. RESULTS: Prevalence of CagA and VacA seropositivity was 90 and 95% in GC, 84 and 84% in DU Hp negative, 25 and 5% in children Hp negative, respectively. CagA and VacA antibody positivity was not significantly different between GC and patients with DU eradicated 10 years before. A true significant positivity was found against children (''t''-Student test; p<0.0001). Statistical difference was found in age between groups p<0.03. CONCLUSIONS: Patients with GC, although Hp negative at present, could be infected by Hp before the appearance of the disease as confirmed by CagA and VacA seropositivity. These data may reinforce the idea to consider Hp as a direct carcinogenetic agent of GC.

Results of a prospective study with high-dose etoposide, thiotepa and carboplatin and peripheral blood stem cell rescue for high-risk stage II-IIIA and selected stage IV breast cancer patients.

AIMS AND BACKGROUND: To investigate the safety and efficacy of a high-dose chemotherapy regimen with etoposide, carboplatin and thiotepa in high-risk stage II-IIIA breast cancer and in responsive metastatic patients. STUDY DESIGN: From April 1992 to December 1998, 24 patients with high-risk stage II-IIIA breast cancer (> or = 9 positive nodes) and 9 responsive metastatic patients were enrolled in the trial. After induction chemotherapy with an anthracycline-based regimen, peripheral blood stem cells were mobilized with cyclophosphamide (7 g/m2) and G-CSF (5-16 microg/kg/s.c./day). The high-dose chemotherapy regimen consisted of etoposide (1000 mg/m2), carboplatin (800 mg/m2) and thiotepa (500 mg/m2). At the end of the high-dose chemotherapy, all stage II-IIIA patients received radiotherapy to the breast or chest wall and draining nodes; stage IV patients were irradiated to sites of disease, if feasible. All ER+ and/or PgR+ patients were treated with hormone therapy. RESULTS: For stage II-IIIA high-risk patients, the median follow-up was 4.36 years (range, 1.93-6.94), and the Kaplan-Meier estimate at 5 years of disease-free survival and overall survival was 54.8 +/- 11% SE and 76.73 +/- 9.4% SE, respectively. For metastatic patients, the median follow-up was 4.93 years (range, 4.15-7.95), and the Kaplan-Meier estimate at 5 years of progression-free survival and overall survival was 22.2 +/- 13.9% SE and 76.2 +/- 14.8% SE, respectively. No treatment-related deaths were observed. CONCLUSIONS: Our results are comparable to those obtained in other high-dose chemotherapy trials but do not seem to be superior to conventional-dose therapy given to similar patients.

Survival, quality of life and breast cancer.

In recent years, evaluating quality of life (QoL) has become increasingly important as an additional measured outcome in cancer clinical trials, in particular in the field of breast cancer. This paper, after a general introduction to the present debate on the methodological issues involved in QoL evaluation, reviews results and open questions regarding the use of this measure in surgical, adjuvant and metastatic studies.

Regional node failure in patients with four or more positive lymph nodes submitted to conservative surgery followed by radiotherapy to the breast.

A retrospective analysis was conducted to evaluate the incidence of nodal failure in a subgroup of patients who had T1-T2 breast cancer and four or more positive nodes. Sixty-four 5 patients ranging in age from 29 to 73 years (median, 51) received conservative surgery followed by radiotherapy to the breast between November 1980 and May 1995. Adjuvant chemotherapy was administered to 56 patients, 27 of whom were also treated with tamoxifen, which was used alone in 5 patients. Three patients received no adjuvant treatment. Sixty-two patients are evaluable for regional node failure. There were 10 nodal failures, 4 in the axillary and 6 in the supraclavicular regions, in 9 patients, at a median of 56.5 and 27 months, respectively. There was no internal mammary node failure. Median follow-up was 72.6 months. The 10-year probability of developing axillary and supraclavicular failure is 13.9 +/- 7.7% and 10.5 +/- 4.1%, respectively. Prognosis was better for patients with axillary and breast recurrence and worse when relapse was in the supraclavicular region. On the basis of our results and data already published in premenopausal patients, we believe that radiotherapy to the supraclavicular region should be considered in patients with four or more positive axillary nodes, after a complete dissection.

Long-term results in patients with advanced epithelial ovarian carcinoma treated with a combination of cisplatin, doxorubicin, and cyclophosphamide.

From 1984 to 1988, thirty-nine untreated patients with epithelial ovarian cancer received Cisplatin 50 mg/m2, Doxorubicin 50 mg/m2, and Cyclophosphamide 750 mg/m2 (CAP), at 3 weekly intervals. All patients had FIGO stage III or IV tumors except 2 patients with stage IIb and IIc, respectively. After initial surgery 23 patients had residual disease > 2 cm in diameter. Twenty-five patients (64%) were evaluable for response to chemotherapy. Objective responses were observed in 13 out of 25 patients (52%, 95% confidence intervals (CI), 32.42% to 71.58%), 6 patients had a cCR (24%) and 7 had a cPR (28%). Seventeen out of the 39 patients (44%) had a second-look laparotomy. A pCR was achieved in 5 out of 17 patients (29%); a pPR was obtained in 8 patients (47%). Median duration of survival was 41,5 months (range 2-107+); median duration of time to failure was 21 months (range 2-107+). Median disease-free survival was 86 months (range 3,5-107+). Eleven patients (28%) are alive and 9 patients (23%) are free of recurrence at median follow-up of 86 months. Only 4 of 11 long-term survivors had a pCR. In univariate analysis, histology, clinical response to chemotherapy, and the presence of ascites at the time of diagnosis, achieved a significant correlation with survival and time to failure (TTF); in addition, TTF was significantly affected by pathological response to induction chemotherapy. The only important predictors of disease-free survival (DFS) were tumor grade and stage of disease. In multivariate analysis, the presence of ascites was the only significant prognostic factor with respect to survival and TTF. Our study confirms the effectiveness of CAP in the treatment of epithelial ovarian cancer and the relatively poor long term prognosis.

Helicobacter pylori-positive duodenal ulcer: a long-term double-blind randomized study in patients healed with H2-receptor antagonists.

BACKGROUND: The NIH Consensus Conference in 1994 (1) concluded that all patients with peptic ulcer disease should be tested and treated for Helicobacter pylori and that further evaluation was needed for patients in remission. MATERIALS AND METHODS: We evaluated in a double blind randomization 30 patients whose duodenal ulcers had been healed with H2-receptor antagonists and who remained in remission on maintenance therapy. After ulcer healing and the presence of H. pylori had been confirmed, these patients were randomized to receive eradication therapy or placebo and were followed for a mean period of 23 months. RESULTS: Almost all patients receiving placebo had ulcer recurrence, whereas the patients treated with antibiotics demonstrate a low recurrence rate. CONCLUSION: These data suggest, for the first time to our knowledge, the importance of treating with antibiotics duodenal ulcer patients whose disease is in remission.