INOVATYON/ ENGOT-ov5 study: Randomized phase III international study comparing trabectedin/pegylated liposomal doxorubicin (PLD) followed by platinum at progression vs carboplatin/PLD in patients with recurrent ovarian cancer progressing within 6-12 months after last platinum line.

BACKGROUND: This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). METHODS: Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). RESULTS: The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). CONCLUSIONS: This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01379989.

A randomized trial of intensive versus minimal surveillance of patients with resected Dukes B2-C colorectal carcinoma.

BACKGROUND: Colorectal cancer is the third most common and the third most lethal cancer in both men and women in developed countries. About 75% of cases are first diagnosed when the disease is classified as localized or regional, undergo potentially curative treatment and enter a post-treatment surveillance program. Although such programs drain significant resources from health systems, empirical evidence of their efficacy is scanty. PATIENTS AND METHODS: Dukes B2-C colorectal cancer patients who had no evidence of disease at the end of their front-line treatment (surgery and adjuvant radiochemotherapy, if indicated) were eligible for the trial and randomized to two different surveillance programs. These programs differed greatly in the frequency of diagnostic imaging. They had similar schedules of physical examinations and carcinoembryonic antigen (CEA) assessments. Patients received baseline and yearly health-related quality-of-life (HR-QoL) questionnaires. Primary outcomes were overall survival (OS) and QoL. RESULTS: From 1998 to 2006, 1228 assessable patients were randomized, 933 with colon cancer and 295 with rectal cancer. More than 90% of patients had the expected number of diagnostic procedures. Median follow-up duration was 62 months [interquartile range (IQR) 51-86] in the minimal surveillance group and 62 months (IQR 50-85) in the intensive group. At primary analysis, 250 patients had recurred and 218 had died. Intensive surveillance anticipated recurrence, as shown by a significant difference in mean disease-free survival of 5.9 months. Comparison of OS curves of the whole intention-to-treat population showed no statistically significant differences. HR-QoL of life scores did not differ between regimens. CONCLUSION: Our findings support the conclusions of other randomized clinical trials, which show that early diagnosis of cancer recurrence is not associated with OS benefit. CLINICALTRIALSGOV: NCT02409472.

Optimal treatment of early-stage ovarian cancer.

BACKGROUND: There is no clear consensus regarding systemic treatment of early-stage ovarian cancer (OC). Clinical trials are challenging because of the relatively low incidence and good prognosis. Initial results of the International Collaborative Ovarian Neoplasm (ICON)1 trial demonstrated benefit in both overall survival (OS) and recurrence-free survival (RFS) with adjuvant chemotherapy. We report results of 10-year follow-up to establish whether benefits are maintained longer term and discuss how this and other available evidence from randomised trials can be used to guide treatment options regarding the need for, and choice of, adjuvant chemotherapy regimen. PATIENTS AND METHODS: ICON1 recruited women with OC following primary surgery in whom there was uncertainty as to whether adjuvant chemotherapy was indicated. Patients were randomly assigned to adjuvant or no adjuvant chemotherapy. Platinum-based chemotherapy was recommended and 87% received single-agent carboplatin. Analyses of long-term treatment benefits and interaction with risk groups were carried out. A high-risk group of women was defined with stage 1B/1C grade 2/3, any stage 1 grade 3 or clear-cell histology. RESULTS: With a median follow-up of 10 years, the estimated hazard ratio (HR) for RFS was 0.69 [95% confidence interval (CI) 0.51-0.94, P = 0.02] and OS 0.71 (95% CI 0.52-0.98, P = 0.04) in favour of chemotherapy. In absolute terms, there was a 10% (60%-70%) improvement in RFS and a 9% (64%-73%) improvement in OS; the benefit of chemotherapy might be greater in high-risk disease (18% improvement in OS). Uncertainty remains about the optimal chemotherapy regimen. The only randomised trial data available are from a subset of 120 stage 1 patients in ICON3 where the treatment difference, comparing carboplatin with carboplatin/paclitaxel was estimated with relatively wide CIs [progression-free survival HR = 0.71 (95% CI 0.39-1.32) and OS HR = 0.98 (95% CI 0.49-1.93)]. CONCLUSIONS: Extended follow-up from ICON1 confirms that adjuvant chemotherapy should be offered to women with early-stage OC, particularly those with high-risk disease. CLINICAL TRIAL NUMBERS: ISRCTN11916376 for ICON1 and ISRCTN57157825 for ICON3.

Final overall survival results of phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients.

BACKGROUND: The CALYPSO phase III trial compared CD (carboplatin-pegylated liposomal doxorubicin (PLD)) with CP (carboplatin-paclitaxel) in patients with platinum-sensitive recurrent ovarian cancer (ROC). Overall survival (OS) data are now mature. METHODS: Women with ROC relapsing > 6 months after first- or second-line therapy were randomised to CD or CP for six cycles in this international, open-label, non-inferiority trial. The primary endpoint was progression-free survival. The OS analysis is presented here. RESULTS: A total of 976 patients were randomised (467 to CD and 509 to CP). With a median follow-up of 49 months, no statistically significant difference was observed between arms in OS (hazard ratio = 0.99 (95% confidence interval 0.85, 1.16); log-rank P = 0.94). Median survival times were 30.7 months (CD) and 33.0 months (CP). No statistically significant difference in OS was observed between arms in predetermined subgroups according to age, body mass index, treatment-free interval, measurable disease, number of lines of prior chemotherapy, or performance status. Post-study cross-over was imbalanced between arms, with a greater proportion of patients randomised to CP receiving post-study PLD (68%) than patients randomised to CD receiving post-study paclitaxel (43%; P < 0.001). CONCLUSION: Carboplatin-PLD led to delayed progression and similar OS compared with carboplatin-paclitaxel in platinum-sensitive ROC.

Systematic lymphadenectomy in ovarian cancer at second-look surgery: a randomised clinical trial.

BACKGROUND: The role of systematic aortic and pelvic lymphadenectomy (SAPL) at second-look surgery in early stage or optimally debulked advanced ovarian cancer is unclear and never addressed by randomised studies. METHODS: From January 1991 through May 2001, 308 patients with the International Federation of Gynaecology and Obstetrics stage IA-IV epithelial ovarian carcinoma were randomly assigned to undergo SAPL (n=158) or resection of bulky nodes only (n=150). Primary end point was overall survival (OS). RESULTS: The median operating time, blood loss, percentage of patients requiring blood transfusions and hospital stay were higher in the SAPL than in the control arm (P<0.001). The median number of resected nodes and the percentage of women with nodal metastases were higher in the SAPL arm as well (44% vs 8%, P<0.001 and 24.2% vs 13.3%, P:0.02). After a median follow-up of 111 months, 171 events (i.e., recurrences or deaths) were observed, and 124 patients had died. Sites of first recurrences were similar in both arms. The adjusted risk for progression and death were not statistically different (hazard ratio (HR) for progression=1.18, 95% confidence interval (CI)=0.87-1.59; P=0.29; 5-year progression-free survival (PFS)=40.9% and 53.8%; HR for death=1.04, 95% CI=0.733-1.49; P=0.81; 5-year OS=63.5% and 67.4%, in the SAPL and in the control arm, respectively). CONCLUSION: SAPL in second-look surgery for advanced ovarian cancer did not improve PFS and OS.

A phase II, randomized trial of neo-adjuvant chemotherapy comparing a three-drug combination of paclitaxel, ifosfamide, and cisplatin (TIP) versus paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap-02 Italian Collaborative Study.

BACKGROUND: The efficacy and tolerability of the regimen containing paclitaxel and cisplatin (TP) in the neo-adjuvant treatment of locally advanced squamous cell cervical cancer are unknown. The TIP regimen (TP plus ifosfamide) showed high efficacy but high toxicity and it is used as an internal control. PATIENTS AND METHODS: In all, 154 patients were randomized to TP (paclitaxel 175 mg/m(2) + cisplatin 75 mg/m(2); n = 80) or TIP (TP + ifosfamide 5 g/m(2); n = 74), three cycles, followed by radical surgery. Pathological response to chemotherapy was classified as optimal [no residual tumor (complete response) or residual disease with < or = 3 mm stromal invasion (PR1)] or suboptimal response. RESULTS: Patient characteristics (TP/TIP): stage IB2 (56%/64%), IIA (18%/14%), IIB (20%/19%), III-IVA (5%/4%) and median age (42 years/45 years). The optimal response rate in the TP group was 25%, 95% confidence interval (CI) = 16% to 37% and 43%, 95% CI = 31% to 55% in the TIP group. Grades 3-4 leukopenia (6%/53%) and neutropenia (26%/76%) were significantly more frequent on TIP. CONCLUSION: TP performance was below expectation since the lower 95% confidence limit of the optimal response rate failed to reach the prespecified minimum requirement of efficacy, i.e. 22%. The TIP regimen confirmed its activity but was associated with higher haematological toxicity than TP.

DeltaNp63 expression is associated with poor survival in ovarian cancer.

BACKGROUND: P63 belongs to the 'p53 family' whose role in cancer progression has been recently revisited in light of the plethora of splicing variants that are generated. We analyzed the expression of the full-length TAp63 gene and its dominant-negative form deltaNp63 in ovarian cancer biopsies to correlate their expression with clinical outcome. MATERIALS AND METHODS: Real-time RT-PCR analysis was used to determine the levels of TAp63 and deltaNp63 in 83 stage I and in 86 stage III ovarian cancer biopsies and in seven human ovarian cancer cell. RESULTS: TAp63 levels were comparable in stage I and stage III, but deltaNp63 levels increased 77-fold in stage III, independently of the p53 status. Patients with high deltaNp63 expression had the worst overall survival (OS); patients with a deltaNp63/TAp63 ratio >2 had a poor OS. Patients with a high deltaNp63/TAp63 ratio were those with a poor response to platinum-based therapy. CONCLUSIONS: Data indicate a role for deltaNp63 as a potential biomarker to predict patient's outcome and tumor progression in ovarian cancer. This would have particularly clinical relevance in ovarian cancer where the high rate of mortality reflects our lack of knowledge of molecular mechanisms underlying cell progression toward malignancy.

Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women.

PURPOSE: A systematic review of randomized clinical trials (RCTs) was undertaken to assess the effectiveness of medical treatment for metastatic breast cancer. METHODS: RCTs published between 1975 and 1997 have been classified according to 12 therapeutic comparisons: (1) polychemotherapy (PCHT) agents versus single agent; (2) PCHT regimens with anthracycline versus PCHT without anthracycline; (3) other PCHT versus cyclophosphamide, methotrexate, and fluorouracil (CMF); (4) chemotherapy (CHT) with epirubicin versus CHT with doxorubicin; (5) CHT versus same CHT delivered with less intensive schedules; (6) other endocrine therapy (OET) versus tamoxifen; (7) OET plus tamoxifen versus tamoxifen alone; (8) OET versus medroxyprogesterone; (9) OET versus aromatase inhibitors; (10) OET versus megestrol; (11) endocrine therapy (ET) versus same ET at lower doses; and (12) CHT plus ET versus CHT. Tumor response rates, mortality hazards ratio (HR) and frequency of severe side effects were the outcome measures. RESULTS: A total of 189 eligible trials (31,510 patients) were identified. All provided response rates and 133 (70%) data or survival curves needed for calculation of the HR. In eight of 12 comparisons, statistically significant differences for response emerged (1, 2, 3, 5, 7, 8, 11, 12); all but no. 8 favored the first term of the comparison. Overall survival analysis showed better results of (a) PCHT versus single-agent CHT (HR=0.82; 95% confidence interval [CI], 0.75 to 0.90); (b) CHT with doxorubicin versus CHT with epirubicin (HR=1.13; 95% CI, 1.00 to 1.27); (c) CHT versus the same CHT delivered with less intensive schedules (HR=0.90; 95% CI, 0.83 to 0.97); (d) ET versus the same ET at lower doses (HR=0.86; 95% CI, 0.77 to 0.97). Quality of life was measured in only 2,995 of 31,510 patients (9.5%). CONCLUSION: Despite some evidence of effectiveness of specific regimens, the relevance of these findings is limited by the modest survival benefit and the lack of evaluation of the quality-of-life impact of these treatments.

Follow-up strategies for women treated for early breast cancer.

BACKGROUND: Follow-up examinations are commonly performed after primary treatment for women with breast cancer. They are used to detect recurrences at an early (asymptomatic) stage. OBJECTIVES: To assess the effectiveness of different policies of follow-up for distant metastases on mortality, morbidity and quality of life in women treated for stage I, II or III breast cancer. SEARCH STRATEGY: We searched, the Breast Cancer Group's specialized register (May 14, 2004), the Cochrane Controlled Trial Register (Cochrane Library Issue 1, 2004), Medline (January 1966 - May 2004) and EMBASE (1988 - May 2004). References from retrieved articles were also checked. SELECTION CRITERIA: All randomised controlled trials (RCTs) assessing the effectiveness of different policies of follow-up after primary treatment were reviewed for inclusion. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and eligibility for inclusion in the review. Data were pooled in an individual patient data meta-analysis for the two RCTs testing the effectiveness of different follow-up schemes. Subgroup analyses were conducted by age, tumour size and lymph node status. MAIN RESULTS: Four RCTs involving 3055 women with breast cancer (clinical stage I, II or III) were included. Two of these involving 2563 women compared follow-up based on clinical visits and mammography with a more intensive scheme including radiological and laboratory tests. After pooling the data, no significant differences in overall survival (hazard ratio 0.96, 95% confidence interval 0.80 to 1.15) or disease-free survival (hazard ratio 0.84, 95% confidence interval 0.71 to 1.00) emerged. No differences in overall survival and disease-free survival emerged in subgroup analyses according to patient age, tumour size and lymph node status before primary treatment. In 1999, 10-year follow-up data became available for Rosselli Del Turco and no significant differences in overall survival were found. One RCT (296 women) compared follow-up performed by a hospital-based specialist to follow-up performed by general practitioners. No significant differences in time to detection of recurrence and quality of life emerged. Patient satisfaction was greater among patients treated by general practitioners. One RCT (196 women) compared regularly scheduled follow-up visits to less frequent visits restricted to the time of mammography. No significant differences emerged in interim use of telephone and frequency of GP's consultations. AUTHORS' CONCLUSIONS: This updated review of RCTs conducted almost 20 years ago suggest that follow-up programs based on regular physical examinations and yearly mammography alone are as effective as more intensive approaches based on regular performance of laboratory and instrumental tests in terms of timeliness of recurrence detection, overall survival and quality of life. In one RCT, follow-up care performed by trained general practitioners working in an organized practice setting had comparable effectiveness to that delivered by hospital-based specialists in terms of quality of life and time to detection of distant metastases.

Inhibition by phospholipid liposomes of the prolactin and cortisol response to insulin hypoglycemia in man.

This study was designed to further investigate the purported dopaminergic activity of phospholipid liposomes (PL) prepared from bovine cerebral extracts, and to obtain further indications about their pituitary or suprapituitary site of action. In eight normal subjects, we have studied the effects of PL administration (250 mg as IV bolus plus additional 250 mg infused IV over a 60-min period), compared to placebo, on the prolactin (PRL), cortisol and growth hormone (GH) response to an insulin tolerance test (ITT). In eight additional subjects, the effects of PL on the PRL and TSH response to TRH were evaluated. PL medication blunted the PRL and cortisol response in the ITT: significant differences, with respect to placebo administration, were observed between mean peak PRL values (51.9 +/- 13.63 SEM vs 83.4 +/- 26.35 ng/ml, P less than 0.05) and mean cortisol values at 120 min time (20.9 +/- 0.67 vs 26.7 +/- 2.46 micrograms/dl, P less than 0.05). In contrast, PL administration did not modify the ITT-related GH rise or the PRL and TSH release in response to TRH. These findings favour the view that PL are endowed with intrinsic biological activity which is dopamine-mediated, and point to the hypothalamus as their primary site of action.

Breast cancer surgery in 30 Italian general hospitals.

The utilization of limited surgery in patients with breast cancer operated between September 1986 and July 1988 was assessed using information collected within a cohort subsequently enrolled in a randomized clinical trial testing the efficacy of post-surgical follow up. Overall 30% had limited surgery, 61% had other more radical procedures and 9% are still undergoing an unnecessary Halsted mastectomy. Several factors were related to the lower likelihood of getting a conservative procedure: geographic distribution, age, level of education, quadrant and nodal state. The paper discusses the implications of these findings in view of the otherwise growing consensus that more radical surgery should be abandoned.

Follow-up strategies for women treated for early breast cancer.

BACKGROUND: Follow-up examinations are commonly performed after primary treatment for women with breast cancer. They are used to detect recurrences at an early (asymptomatic) stage. OBJECTIVES: To assess the effectiveness of different policies of follow-up for distant metastases on mortality, morbidity and quality of life in women treated for early breast cancer. SEARCH STRATEGY: We searched the Breast Cancer Groups specialised register, the Cochrane Controlled Trials Register ( Cochrane Library Issue 4, 1999), MEDLINE (January 1975-September 1999) and EMBASE (1988-September 1999) using "Breast Neoplasms" and "follow-up". References from retrieved articles were also checked, as were the lists of presentations from recent breast cancer meetings. SELECTION CRITERIA: All randomised controlled trials (RCTs) assessing the effectiveness of different policies of follow-up after primary treatment were reviewed for inclusion. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and eligibility for inclusion in the review. Data were pooled in an individual patient data meta-analysis for the two RCTs testing the effectiveness of different follow-up schemes. Subgroup analyses by age, tumour size and lymph node status before primary treatment are also presented. MAIN RESULTS: Four RCTs involving 3204 women with early breast cancer (clinical stage I, II or III) have been included. Two RCTs involving 2563 women compared follow-up based on clinical visits and mammography with a more intensive scheme including radiological and laboratory tests. After pooling the data, no significant differences in overall survival (hazard ratio 0.96, 95% confidence interval 0.80 to 1.15) or disease-free survival (hazard ratio 0.84, 95% confidence interval 0.71 to 1.00) emerged. No differences in overall survival and disease-free survival emerged in subgroup analyses according to patient age, tumour size and lymph node status before primary treatment. One RCT (296 women) compared follow-up performed by a hospital-based specialist to follow-up performed by general practitioners. No significant differences in time to detection of recurrence and quality of life emerged. One RCT (196 women) compared regularly scheduled follow-up visits to less frequent visits restricted to the time of mammography. No significant differences emerged in interim use of telephone and frequency of GP's consultations. REVIEWER'S CONCLUSIONS: Follow-up programs based on regular physical examinations and yearly mammography alone appear to be as effective as more intensive approaches based on regular performance of laboratory and instrumental tests in terms of timeliness of recurrence detection, overall survival and quality of life. In one RCT, follow up care performed by general practitioners had comparable effectiveness to that delivered by hospital based specialists in terms of quality of life and time to detection of distant metastases.

Trends in patterns of care for breast cancer in Italy (1979-1987).

We reviewed care delivered to about 2,500 breast cancer patients in general hospitals over the period 1979-1987 using data from three surveys. The most important and consistent failure was in diagnostic timeliness: about one out of four patients was diagnosed six or more months after the first symptom leading to an almost doubled probability of being diagnosed with more advanced disease. Acceptance of treatment recommendations seemed less satisfactory for surgery than for adjuvant treatments. Conservative surgery still appeared to have limited acceptance for patients with small primary tumor (21 and 23% in 1983 and 1987, respectively) although, starting 1983, there was a shift from the Halsted to the Patey type of radical mastectomy. Follow-up was routine in most node-negative patients and adjuvant chemotherapy was already well established treatment for most pre-menopausal node-positive women (64, 79 and 76% in 1979, 1983 and 1987, respectively). Some form of adjuvant treatment in post-menopausal node-positive women was already present in 1983 but became more widespread in 1987 (82%): this being mostly accounted for by the increase in the use of tamoxifen (delivered alone or in combination with chemotherapy to 53% of women). Overall, our results suggest that areas of care more dependent on organization or doctors' and patients' education (i.e. diagnostic timeliness and accessibility) are those where deficiencies seen to be least amenable to change in the absence of concerted intervention. Among more narrowly defined clinical issues, there appeared to be some dissonance between the rapid acceptance of adjuvant treatments and the still slow pace of acceptance of less aggressive procedures by surgeons.

Quality of care assessment for breast cancer: how to measure benefits of prevention and therapy in oncology.

Over the last few years evaluation of quality of diagnostic and therapeutic care has become one of the most controversial and fastest growing fields of research in many areas of medicine. In this situation, oncology represents a model case as the conditions in which new therapeutic strategies are tested and implemented largely differ from routine practice, both in terms of availability of sophisticated technology and comparability of patient populations. The promising role of health care research for the understanding of factors through which research advances can be generalized to routine clinical practice has only recently being appreciated. From this point of view, the paper discusses the rationale and key findings of a multi-annual++ evaluation program on breast cancer care, underway in Italy since 1980. Special attention is given to how results (such as data on diagnostic delay or non-adherence to recommended treatment guidelines) can be used for the implementation of educational programs, controlled studies and ad hoc demonstration projects.

Expression of DNA repair genes in ovarian cancer samples: biological and clinical considerations.

The purpose of this study was to investigate retrospectively the mRNA expression of genes involved in different DNA repair pathways implicated in processing platinum-induced damage in 171 chemotherapy-naïve ovarian tumours and correlate the expression of the different genes with clinical parameters. The expression of genes involved in DNA repair pathways (PARP1, ERCC1, XPA, XPF, XPG, BRCA1, FANCA, FANCC, FANCD2, FANCF and PolEta), and in DNA damage transduction (Chk1 and Claspin) was measured by RT-PCR in 13 stage I borderline and 77 stage I and 88 III ovarian carcinomas. ERCC1, XPA, XPF and XPG genes were significantly less expressed in stage III than in stage I carcinoma; BRCA1, FANCA, FANCC, FANCD2 gene expressions were low in borderline tumours, higher in stage I carcinomas and lower in stage III samples. High levels of ERCC1, XPA, FANCC, XPG and PolEta correlated with an increase in Overall Survival (OS) and Progression Free Survival (PFS), whilst high BRCA1 levels were associated with PFS on univariate analysis. With multivariate analyses no genes retained an association when adjusted by stage, grade and residual tumour. A tendency towards a better PFS was observed in patients with the highest level of ERCC1 and BRCA1 after platinum-based therapy than those given both platinum and taxol. The expression of DNA repair genes differed in borderline stage I, stage I and stage III ovarian carcinomas. The role of DNA repair genes in predicting the response in ovarian cancer patients seems far from being established.

A phase II randomised clinical trial comparing cisplatin, paclitaxel and ifosfamide with cisplatin, paclitaxel and epirubicin in newly diagnosed advanced epithelial ovarian cancer: long-term survival analysis.

To test the feasibility and efficacy of epirubicin and ifosfamide added to first-line chemotherapy with cisplatin and paclitaxel in a phase II randomised clinical trial. Patients with histologically proven epithelial ovarian cancer were randomly assigned to receive first-line polychemotherapy with cisplatin/paclitaxel/epirubicin (CEP) or cisplatin/paclitaxel/ifosfamide (CIP) for six cycles every 21 days. Two hundred and eight patients were randomised between the two treatment arms and the median number of cycles per patient was six. Toxicity was predominantly haematological with both regimens; however, anaemia, leucopaenia, neutropaenic fever and use of granulocyte colony-stimulating factors and transfusion were significantly more frequent in the CIP treatment arm. Response rates were 85% (95% confidence interval (CI) 77-93%) in the CIP arm and 90% (95% CI 84-96%) in the CEP arm; complete response rates were 48 and 52%. After a median follow-up of 82 months, median overall survival (OS) was 51 and 65 months; 5-year survival rates were respectively 43 and 50%. In this clinical trial, both regimens showed good efficacy, but toxicity was heavier with the CIP regimen. Considering that more than 50% of patients were suboptimally debulked after the first surgery, OS seems to be longer than is commonly reported. This unexpected finding might be a consequence of the close surgical surveillance and aggressive chemotherapeutic approach.

Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial.

Patients with high-risk endometrial carcinoma (stage IcG3, IIG3 with myometrial invasion >50%, and III) receive adjuvant therapy after surgery but it is not clear whether radiotherapy (RT) or chemotherapy (CT) is better. We randomly assigned 345 patients with high-risk endometrial carcinoma to adjuvant CT (cisplatin (50 mg m(-2)), doxorubicin (45 mg m(-2)), cyclophosphamide (600 mg m(-2)) every 28 days for five cycles, or external RT (45-50 Gy on a 5 days week(-1) schedule). The primary end points were overall and progression-free survival. After a median follow-up of 95.5 months women in the CT group as compared with the RT group, had a no significant hazard ratio (HR) for death of 0.95 (95% confidence interval (CI), 0.66-1.36; P = 0.77) and a nonsignificant HR for event of 0.88 (95% CI, 0.63-1.23; P = 0.45). The 3, 5 and 7-year overall survivals were 78, 69 and 62% in the RT group and 76, 66 and 62% in the CT group. The 3, 5 and 7-year progression-free survivals were, respectively, 69, 63 and 56 and 68, 63 and 60%. Radiotherapy delayed local relapses and CT delayed metastases but these trends did not achieve statistical significance. Overall, both treatments were well tolerated. This trial failed to show any improvement in survival of patients treated with CT or the standard adjuvant radiation therapy. Randomised trials of pelvic RT combined with adjuvant cytotoxic therapy compared with RT alone are eagerly awaited.

Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis.

No randomised trials have addressed the value of systematic aortic and pelvic lymphadenectomy (SL) in ovarian cancer macroscopically confined to the pelvis. This study was conducted to investigate the role of SL compared with lymph nodes sampling (CONTROL) in the management of early stage ovarian cancer. A total of 268 eligible patients with macroscopically intrapelvic ovarian carcinoma were randomised to SL (N=138) or CONTROL (N=130). The primary objective was to compare the proportion of patients with retroperitoneal nodal involvement between the two groups. Median operating time was longer and more patients required blood transfusions in the SL arm than the CONTROL arm (240 vs 150 min, P<0.001, and 36 vs 22%, P=0.012, respectively). More patients in the SL group had positive nodes at histologic examination than patients on CONTROL (9 vs 22%, P=0.007). Postoperative chemotherapy was delivered in 66% and 51% of patients with negative nodes on CONTROL and SL, respectively (P=0.03). At a median follow-up of 87.8 months, the adjusted risks for progression (hazard ratio [HR]=0.72, 95%CI=0.46-1.21, P=0.16) and death (HR=0.85, 95%CI=0.49-1.47, P=0.56) were lower, but not statistically significant, in the SL than the CONTROL arm. Five-year progression-free survival was 71.3 and 78.3% (difference=7.0%, 95% CI=-3.4-14.3%) and 5-year overall survival was 81.3 and 84.2% (difference=2.9%, 95% CI=-7.0-9.2%) respectively for CONTROL and SL. SL detects a higher proportion of patients with metastatic lymph nodes. This trial may have lacked power to exclude clinically important effects of SL on progression free and overall survival.