Cancer Biology and Survival Analysis in Cancer Trials: Restricted Mean Survival Time Analysis versus Hazard Ratios.

Hazard ratios are commonly used when comparing survival between two groups and make the assumption that the relative event rates do not change markedly during follow-up, i.e. that event rates are proportional. However, there is currently debate about the use of the proportional hazards assumption to summarise the treatment effect in survival analysis compared with restricted mean survival time (RMST) analysis, particularly in cancer trials. In many situations it is unrealistic to assume that relative event rates in two groups will be proportional throughout follow-up and, hence, RMST analysis, which does not make this assumption, may be preferable. Several benefits of the latter approach have been identified but the biological perspective is not often discussed. Biological features such as the patterns of tumour growth and response can also contribute to assessing the relative merit of these two methods; such biological considerations are the subject of this paper. The observation that the most commonly observed approximation to the underlying distribution of time to event data, the lognormal distribution, does not reliably show proportional hazards in the comparison of two groups, lends weight to a statistical approach that is not based on proportional hazards. The proportional hazards assumption should be viewed more critically when estimating treatment effects. An optimum approach may be to include both proportional hazards analysis and RMST analysis when comparing time to event endpoints.

Assessment of microtubule-associated protein (MAP)-Tau expression as a predictive and prognostic marker in TACT; a trial assessing substitution of sequential docetaxel for FEC as adjuvant chemotherapy for early breast cancer.

The TACT trial is the largest study assessing the benefit of taxanes as part of adjuvant therapy for early breast cancer. The goal of this translational study was to clarify the predictive and prognostic value of Tau within the TACT trial. Tissue microarrays (TMA) were available from 3,610 patients. ER, PR, HER2 from the TACT trial and Tau protein expression was determined by immunohistochemistry on duplicate TMAs. Two parallel scoring systems were generated for Tau expression ('dichotomised' vs. 'combined' score). The positivity rate of Tau expression was 50 % in the trial population (n = 2,483). Tau expression correlated positively with ER (p < 0.001) and PR status (p < 0.001); but negatively with histological grade (p < 0.001) and HER2 status (p < 0.001). Analyses with either scoring systems for Tau expression demonstrated no significant interaction between Tau expression and efficacy of docetaxel. Contrary to the hypothesis that taxane benefit would be enriched in Tau negative/low patients, the only groups with a suggestion of a reduced event rate in the taxane group were the HER2-positive, Tau positive subgroups. Tau expression was seen to be a prognostic factor on univariate analysis associated with an improved DFS, independent of the treatment group (p < 0.001). It had no prognostic value in ER-negative tumours and the weak prognostic effect of Tau in ER-positive tumours (p = 0.02) diminished, when considering ER as an ordinal variable. On multivariable analyses, Tau had no prognostic value in either group. In addition, no significant interaction between Tau expression and benefit from docetaxel in patients within the PR-positive and negative subsets was seen. This is now the second large adjuvant study, and the first with quantitative analysis of ER and Tau expression, failing to show an association between Tau and taxane benefit with limited utility as a prognostic marker for Tau in ER-positive early breast cancer patients.

Significance of tumour calcification in ovarian carcinoma.

The purpose of this study was to assess the pattern and significance of tumour calcification in ovarian carcinoma. Patients with calcifying ovarian carcinoma were identified from radiological reports. Their tumour characteristics, serum calcium levels, treatment and survival were compared with a control group of patients with non-calcifying disease. Patterns and distribution of calcification were assessed. Available serial CT scans were reviewed for changes in both soft-tissue and calcified disease according to RECIST (response evaluation criteria in solid tumours) criteria where feasible. Temporal changes in calcification were correlated with changes in soft tissue disease and CA125 levels. The calcified group numbered 122 (22 other patients had calcifying tumour but insufficient clinical data). Calcification in ovarian carcinoma had a prevalence of 8% (144/1721) in our series. There was a significant difference (p<0.001) between the two groups in the distribution of histological type, with serous tumours being more common in the calcified group (74/122 (61%)) than in the controls (509/1498 (34%)). The calcified tumour patients tended to have lower grade disease (p<0.001). No differences between the groups were found for age, treatment or serum calcium levels. Distribution of calcification was diffusely peritoneal in 34 patients, in association with a pelvic mass in 15, nodal in 11 and within the anterior abdominal wall in 2. There was no correlation between changes in calcification on serial CT scans and corresponding CA125 levels. In conclusion, calcification tends to occur most commonly in serous cystadenocarcinomata and in tumours of lower grade. Changes in calcification cannot be used as a marker of disease response.

Epirubicin, cisplatin and protracted venous infusion 5-Fluorouracil chemotherapy for advanced salivary adenoid cystic carcinoma.

AIMS: Adenoid cystic carcinoma (ACC) is a rare tumour that usually arises in the salivary glands. Initial management is surgery often combined with adjuvant radiotherapy. Chemotherapy is reserved for treatment of symptomatic recurrence. We evaluated the combination of epirubicin, cisplatin and protracted venous infusion 5-fluorouracil (ECF) in the management of ACC. MATERIALS AND METHODS: Patients referred for treatment of advanced, symptomatic ACC were considered. The drugs given were epirubicin 50 mg/m(2) 3-weekly, cisplatin 60 mg/m(2) 3-weekly and protracted venous infusion 5-fluorouracil 200 mg/m(2)/day. RESULTS: Eight patients (median age 46 years) received a median of five cycles of chemotherapy. All patients had had previous surgery, seven had had previous radiotherapy and one had had previous chemotherapy. One patient showed a partial response (duration 34 months) and five showed stable disease (median duration 13.6 months [6.8-15.9+ months]). Median survival was 27 months (3.5-62.3 months). CONCLUSIONS: The activity of ECF in ACC of the head and neck seems to be similar to the combination of cisplatin and 5-fluorouracil and single-agent epirubicin.

Sweat-gland tumours: a clinical review of cases in one centre over 20 years.

AIMS: Sweat-gland tumours (SGTs) are uncommon, but malignant varieties are very rare. We have added our data on 30 new cases seen at the Royal Marsden NHS Foundation Trust to the published literature, particularly concentrating on clinical issues. We include a literature review. MATERIALS AND METHODS: The Royal Marsden NHS Foundation Trust database was searched for cases of SGT from 1972. Data were collected on all cases, including patient demographics and tumour characteristics, treatment and outcome. RESULTS: Thirty cases were confirmed histologically to be SGTs. Fourteen were malignant, 15 benign and the degree of malignancy in one was histologically indistinguishable. Mean age was 55 years (64 for malignant, 47 for benign tumours). The 15 patients with benign tumours were almost all treated with complete excision. Those with local relapse underwent successful re-excision. Their 5-year disease-free survival was 78% and cause-specific survival was 100%. Twelve of the 14 malignant tumours had localised disease at diagnosis, one had nodal disease and one had metastatic tumour nodules. All except one were treated with wide local excision. The patient with nodal involvement also had a lymph-node dissection. Two received adjuvant radiotherapy to the tumour bed. One received a melphalan limb perfusion. Eight of the 14 had no relapse. Six had locoregional relapse, and four of these also developed distant metastases. Visceral disease was always fatal. Radiotherapy and chemotherapy at relapse were unsuccessful. Five-year disease-free survival was 45%, and cause-specific survival was 57%. CONCLUSION: These rare tumours should be treated initially with complete wide local excision. In malignant tumours, lymph-node involvement is a poor prognostic sign. Wide local excision remains the primary treatment. Adjuvant radiotherapy may be useful in high-risk cases.

Gefitinib (ZD1839, Iressa) as palliative treatment in recurrent or metastatic head and neck cancer.

To assess the level of activity and toxicity of gefitinib (ZD1839, Iressatrade mark) in a population of patients with locally recurrent and/or metastatic head and neck cancer. Patients were recruited into an expanded access programme through the multidisciplinary head and neck clinics at the Royal Marsden and St George's Hospitals. Patients were required to have received at least one course of standard systemic chemotherapy or radiation therapy, or be medically unfit for chemotherapy. Patients were commenced on single-agent gefitinib at a dose of 500 mg day(-1). Clinical, symptomatic and radiological response, time to progression (TTP), survival and toxicity were recorded. A total of 47 patients were enrolled (35 male and 12 female) with a median age of 62 years (range 18-93 years). The observed clinical response rate was 8% with a disease control rate (complete response, partial response, stable disease) of 36%. In all, 34% of patients experienced an improvement in their symptoms. The median TTP and survival were 2.6 and 4.3 months, respectively. Acneiform folliculitis was the most frequent toxicity observed (76%) but the majority of cases were grade 1 or 2. Only four patients experienced grade 3 toxicity of any type (all cases of folliculitis). Gefitinib was well tolerated and yielded symptomatic improvement in one-third of patients. However, this agent appeared to possess limited antitumour activity in this group of patients with head and neck cancer in whom the objective response rate, median TTP and survival were all lower than has been reported in a previous study.

Neoadjuvant vinorelbine/epirubicin (VE) versus standard adriamycin/cyclophosphamide (AC) in operable breast cancer: analysis of response and tolerability in a randomised phase III trial (TOPIC 2).

BACKGROUND: Vinorelbine is active and well tolerated against advanced breast cancer but there are no published efficacy studies in early breast cancer. We have therefore carried out a randomised phase III neoadjuvant trial in operable breast cancer. PATIENTS AND METHODS: Patients with > or =3 cm operable breast carcinoma were randomised to receive either vinorelbine 25 mg/m(2) on days 1 and 8 and epirubicin 60 mg/m(2) on day 1, 3 weekly for six cycles (VE) or doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) i.v. on day 1, 3 weekly for six cycles (AC), prior to standard local therapy, and adjuvant endocrine therapy as appropriate. RESULTS: A total of 451 patients were randomised. Results for AC and VE, respectively, were: overall clinical response 73% and 74%, complete clinical remission 20% and 24%, pathological complete remission 12% and 12%, mastectomy rate 52% and 55%. None of these differences were significant. Dose reduction was required in 8% for AC and 20% for VE (P <0.001) (GSCF support not used). Significantly more grade 3/4 toxicity for nausea, vomiting and alopecia (despite scalp cooling) was seen for AC compared with VE but significantly less grade 3/4 thrombophlebitis and neuropathy. CONCLUSIONS: Neoadjuvant VE is as effective as AC in early breast cancer and was better tolerated except for thrombophlebitis and neuropathy.

The leukemic presentation of mantle-cell lymphoma: disease features and prognostic factors in 58 patients.

Mantle-cell lymphoma (MCL) is a B-cell malignancy with distinct molecular genetics and pathological features. Peripheral blood involvement has been reported with variable frequency, but information on the natural history of cases presenting with leukemia is lacking. This study aimed to determine the clinical and prognostic features of such cases. We studied clinical features, tumor characteristics, prognostic factors and outcome in 58 patients with leukemic presentation of MCL. Diagnosis was based on morphology, immunophenotype, presence of t(11;14), histology and cyclin D1 expression. The median age was 62 years and male:female 2.4:1. Presenting features included splenomegaly (74%), lymphadenopathy (45%), hepatomegaly (17%) and, in a minority, gastro-intestinal involvement or involvement of Waldeyer's ring; 10% had lymphocytosis alone. Six patients developed central nervous system disease. Median lymphocyte count was 58 x 10(9)/l, 55% had anemia and 17% had thrombocytopenia. Morphology of peripheral blood showed small-cell MCL in 15% of cases, typical MCL in 46% and blastoid MCL in 39%. Immunological markers showed a typical phenotype (CD5+ CD23 -) in 68%, and atypical phenotypes, CD5- CD23- in 17% or CD5+ CD23+ in 15%. CLL scores were 0, 1 or 2 in 96%. Median overall survival was 36 months. Good response to first-line treatment (P = 0.0008) and splenomegaly (P = 0.03) were favorable prognostic factors, while other features including morphology and CD38 expression had no impact on survival or treatment response. This analysis demonstrates that except for splenomegaly, survival of MCL patients presenting with leukemia is not significantly influenced by clinical or tumor characteristics. Splenectomy is a useful treatment option in this group of patients.

A prognostic index that predicts outcome following palliative whole brain radiotherapy for patients with metastatic malignant melanoma.

To determine the outcome of patients with metastatic malignant melanoma (MMM) treated with palliative whole brain radiotherapy (WBRT) and to identify factors that predict treatment outcome to assist future trial design, a retrospective study was performed on patients with MMM who received WBRT at the Royal Marsden Hospital between 1998 and 2003. Data regarding patient factors, tumour factors and survival were collected. A total of 112 patients were identified and full data were available for 102 patients. The median age was 53 years (range 25-81 years), 66.7% were male and 33.3% female. The median dose prescribed was 20 Gy in five fractions as a mid-plane dose. The median survival after WBRT for the whole group was 51 days (range 3-1386). In an attempt to define prognostic groups, we used the validated RTOG recursive partitioning analysis (RPA) classification for brain metastasis (class 1: Karnofsky Performance Score (KPS) >/=70%, age <65 years with no extracranial metastasis; class 3: KPS <70%; class 2: all others). The median survivals were 151, 71 and 21 days for RPA class 1, 2 and 3, respectively (P<0.001). Multivariate analysis showed that RPA class, leptomeningeal involvement, presence and number of extracranial metastatic sites and progressive disease in the brain on imaging before WBRT are important independent predictive factors. A prognostic index was derived from these factors that allowed identification of patients unlikely to benefit from WBRT. In conclusion, the RTOG RPA classification is valid when applied to patients with MMM. Patients in RPA class 1 and good prognosis class 2 are likely to benefit from palliative WBRT and should be considered for entry into trials that aim to improve duration of response. We identified that patients with RPA class 3, leptomeningeal involvement or RPA class 2 with poor prognostic index are unlikely to benefit from palliative WBRT.

A novel continuous infusional 5-fluorouracil-based chemotherapy regimen compared with conventional chemotherapy in the neo-adjuvant treatment of early breast cancer: 5 year results of the TOPIC trial.

BACKGROUND: To compare the efficacy of continuous infusional 5-fluorouracil (5-FU)-based chemotherapy against conventional bolus chemotherapy in the preoperative treatment of patients with large operable early breast cancer. PATIENTS AND METHODS: Four hundred and twenty-six women with histologically proven 3 cm invasive early breast cancer were randomised to receive pre-operative infusional 5-FU 200 mg/m(2) by daily 24 h continuous infusion via a Hickman line for 18 weeks with epirubicin 60 mg/m(2) intravenous (i.v.) bolus on day 1 and cisplatin 60 mg/m(2) i.v. bolus on day 1, both repeating 3-weekly (infusional ECisF), or conventional bolus doxorubicin 60 mg/m(2) i.v. on day 1 and cyclophosphamide 600 mg/m(2) i.v. on day 1, both repeating 3-weekly (AC), both schedules for six courses. Patients subsequently had local therapy (surgery or radiotherapy or both) and tamoxifen 20 mg orally daily as appropriate. RESULTS: The 5 year results for AC and infusional ECisF, respectively, were as follows: overall response, 75% and 77%; complete clinical remission, 31% and 34%; pathological complete remission (pathCR), 16% for both; and pathCR with residual ductal carcinoma in situ (DCIS), 25% and 24%. Mastectomy rates were 37% and 34%, respectively. Five-year overall survival was 74% for AC and 82% for infusional ECisF (hazard ratio 0.76, 95% confidence interval 0.51-1.13; P = 0.18). Both treatments were well tolerated. Grade III/IV lethargy, vomiting, alopecia and plantar-palmar erythema were significantly greater for infusional ECisF; grade III/IV leucopenia was significantly greater for AC. CONCLUSIONS: Preoperative continuous infusional 5-FU-based chemotherapy is no more active than conventional AC for early breast cancer; with a median 5 year follow-up, the infusion-based schedule shows a non-significant trend towards improved survival.

Sample size tables for exact single-stage phase II designs.

Tables for single-phase II trials based on the exact binomial distribution are presented. These are preferable to those generated using Fleming's design, which are based on the normal approximation and can give rise to anomalous results. For example, if the upper success rate is accepted, the lower success rate, which the trial is designed to reject, may be included in the final confidence interval for the proportion being estimated.

An audit of outcome of adjuvant post-operative radiotherapy for 52 women with stage II carcinoma of the endometrium.

A retrospective review was undertaken of the medical records of 52 women with stage II carcinoma of the endometrium who received adjuvant radiotherapy following surgery. The information was obtained from medical notes and a hospital database. Actuarial disease-free survival was 68% at 5 years for those women with stage IIA disease, and 70% at 5 years for those women with stage IIB disease. 6 of the women (11.5%) had side effects from treatment. In contrast to the literature, the only statistically significant prognostic factor in this study was histological differentiation; patients with poorly differentiated tumours fared worse (p = 0.05). This may indicate that a greater number than 52 women is needed to demonstrate weaker prognostic factors such as substage. A larger review is being undertaken of the remaining women recorded on the database, with stage I, III and IV disease.

GM-CSF with biochemotherapy (cisplatin, DTIC, tamoxifen, IL-2 and interferon-alpha): a phase I trial in melanoma.

BACKGROUND: Ineffective tumour antigen processing is recognised as an important cause of failure of immunotherapy in melanoma. GM-CSF may augment the cytotoxic lymphocyte response by activating antigen-presenting cells. This study evaluates a schedule combining GM-CSF with biochemotherapy. PATIENTS AND METHODS: Nineteen patients with advanced malignant melanoma received cisplatin (25 mg/m2 days 1-3). dacarbazine (220 mg/m2 days 1-3), interleukin-2 (9 MIU/m2/24 h) and interferon-alpha2b (5 MIU/m2) both days 6-10 and days 17-21, and tamoxifen 40 mg/day continuously. Subcutaneous GM-CSF was given in escalating doses to three cohorts: 1) 450 microg/m2 days 4-5 and 15-16; 2) as 1) plus 225 microg/m2 days 6-10 and 17-21; 3) 450 microg/m2 days 4-10 and 15-21. Each cycle was 28 days. RESULTS: Constitutional side effects were the major non-haematological toxicity and lymphopaenia the main haematological toxicity. Six patients responded (32%, 95% confidence interval: 13%-57%), two patients had complete remission. There was an apparent trend for increasing responses with increasing GM-CSF dose; zero of six responses in cohort 1, two of seven in cohort 2 and three of six in cohort 3 (P = 0.016). Median overall survival was 6.2 months. Increasing GM-CSF doses significantly increased serum concentrations of neopterin and TNF-alpha. CONCLUSIONS: The combination of GM-CSF with biochemotherapy is feasible and there appears to be a dose-response relationship with GM-CSF in terms of host immunological response, and possibly clinical efficacy.

Pelvic nerve plexus trauma at radical hysterectomy and simple hysterectomy: the nerve content of the uterine supporting ligaments.

BACKGROUND: A major cause of the pelvic morbidity after a radical hysterectomy (RH) is thought to be damage to the pelvic nerve plexus, but direct evidence is lacking. We set out to determine the nerve content of the uterosacral ligaments (USLs) and cardinal ligaments (CLs) at the level at which they are divided during a radical hysterectomy and a simple hysterectomy. METHODS: Intraoperative cross-sectional biopsies were collected from the lateral third of the uterosacral ligaments (USLs) and cardinal ligaments (CLs) in 20 women undergoing radical hysterectomy (RH) and from the uterine insertion of these ligaments in 11 women undergoing a simple hysterectomy. Quantitative immunocytochemistry was utilized to demonstrate and quantify the nerve content of the uterine supporting ligaments at the level at which they are divided in a RH and in a simple hysterectomy. Indirect immunofluorescence staining of frozen cryostat sections was performed using primary antibodies to PGP 9.5 (a pan-neuronal marker). A computer-assisted image analyzer measured the percentage area of immunoreactivity (PAI) that was used to quantify the nerve density. Confocal microscopy was used to determine the composition and spatial arrangement of nerve fibers in the ligaments. RESULTS: The PAI was significantly greater in the RH biopsies than in the simple hysterectomy biopsies, for both the CLs (P < 0.001) and the USLs (P < 0.001). In the RH biopsies, more nerve tissue was present in the USL than CL (P = 0.01), and compared with the CL more of the nerve fibers in the USL were concentrated in large trunks. Excluding these trunks and autonomic ganglia, the free nerve content of the USL was lower than that of the CL (P < 0.001). The presence of nerve trunks, autonomic ganglia, and free nerve fibers within the lateral third of the USL and CL is consistent with extension of the inferior hypogastric plexus along these ligaments to the pelvic organs. CONCLUSIONS: The uterine supporting ligaments contain autonomic nerves and ganglia, as extensions of the inferior hypogastric plexus. The USLs have a greater nerve density than the CLs. Because RH disrupts more nerve tissue than a simple hysterectomy, these data provide further evidence for the neurogenic etiology of pelvic morbidity after RH.

Prognosis and surgical management of patients with palpable inguinal lymph node metastases from melanoma.

BACKGROUND: The appropriate management of melanoma metastatic to inguinal lymph nodes remains controversial. The aim of this study was to identify disease- and treatment-related factors that influence the outcome of patients undergoing therapeutic groin dissection for clinically detectable melanoma lymph node metastases. METHODS: A retrospective analysis was performed on data collected from the case records of patients who had a therapeutic inguinal lymph node dissection performed between 1984 and 1998. RESULTS: Some 132 patients were suitable for inclusion. Sixty patients had superficial inguinal lymph node dissection (SLND) and 72 had combined superficial inguinal and pelvic lymph node dissection (CLND). There was no difference in postoperative morbidity or major lymphoedema between SLND and CLND. The overall survival rate was 34 per cent at 5 years. On univariate analysis, age (P = 0.003), the number of involved superficial lymph nodes (P = 0.001) and the presence of extracapsular spread (P = 0.003) were found to have a significant impact on survival. The presence or absence of pelvic lymph node metastases in patients who had CLND was a significant prognostic factor for survival (5-year survival 19 versus 47 per cent; P = 0.015). CONCLUSION: The prognosis of patients with clinically detectable melanoma metastases to the groin is variable and related to the biological characteristics of each case. CLND provided additional prognostic information and optimal regional control with no increased morbidity compared with SLND.

A case-control study confirms that microsatellite assay can identify patients at risk of developing oral squamous cell carcinoma within a field of cancerization.

Distinguishing true precursor lesions on the basis of clinical or histological features alone is unreliable but is important so that appropriate intervention can be instigated. Preliminary studies have shown that a microsatellite assay may provide important new prognostic information. To build on these observations, we have performed a case-control study to establish whether we can be confident about incorporating this new information into clinical practice. We have determined the frequency of allelic imbalance (AI) within key chromosomal regions, by matching 39 cases with dysplastic oral lesions that developed a tumor on the same side of the mouth, for as many variables as possible, with controls presenting with similar lesions that did not progress to malignancy when followed for the same period. Our findings confirm that the group that developed tumor had precursor lesions that harbor AI at more loci (P = 0.002). However, no consistent patterns of AI were associated with the three grades of dysplasia: mild, moderate, and severe. One-third of the tumors developed at the same site as the dysplastic lesion and two-thirds at a different site, which revealed that the presence of these aberrations in a dysplastic lesion provided information about the risk of malignant change within a larger field. This suggests that the process of field cancerization is more widespread than previously recognized. On the basis of these findings, we advocate complete excision of all suspicious areas that show AI at two or more key loci, regardless of the degree of dysplasia. However, because the remaining mucosa is also "at risk," these cases should also be targeted to receive dietary advice and chemoprevention, to minimize their risk of tumor formation at a distant site.

Combining platinum, paclitaxel and anthracycline in patients with advanced gynaecological malignancy.

Two meta-analyses have suggested that the addition of an anthracycline to platinum-based chemotherapy may improve survival in advanced ovarian cancer, and two randomised trials have demonstrated superiority of paclitaxel over cyclophosphamide in platinum combinations. A combination of platinum, anthracycline and paclitaxel would, therefore, be a reasonable experimental arm of any future randomised trial in patients with epithelial ovarian carcinoma (EOC). Patients who required chemotherapy for EOC but were ineligible for standard trials or had other gynaecological tumours that required similar platinum-based chemotherapy were considered for this pilot. The platinum/anthracycline/paclitaxel regimen (G-CAT) was given 3-weekly and consisted of doxorubicin 50 mg/m(2) or epirubicin 60 mg/m(2) intravenously (i.v.) bolus, paclitaxel 175 mg/m(2) (i.v.) over 3 h and either cisplatin 75 mg/m(2) (i.v.) or carboplatin AUC 6, with granulocyte colony-stimulating factor (G-CSF) at the neutrophil nadir. Different combinations were used in order to determine the least toxic regimen. Toxicity and response were assessed according to CTC and WHO criteria, respectively. 26 patients entered the study, 13 with EOC and 13 with other gynaecological cancers (peritoneal, fallopian tube, mixed Mullerian). Median age was 49 years (range: 27-67). 8 patients received carboplatin/doxorubicin/paclitaxel, 8 cisplatin/doxorubicin/paclitaxel and 10 carboplatin/epirubicin/paclitaxel. A total of 135 cycles of chemotherapy were delivered, with a median of 6 cycles per patient (range: 2-6). 54 (40%) cycles required G-CSF support and 17 (65%) patients required at least one dose reduction. All patients experienced grade 4 neutropenia and 13 (50%) patients developed grade 3-4 thrombocytopenia (12 of whom had received carboplatin). There were 4 (15%) patients with grade 3/4 infections but no septic deaths. Non-haematological toxicities were manageable, lethargy occurred in 75% of cisplatin-treated patients. Grade 1/2 cardiotoxicity, as assessed pre- and post-treatment by left ventricular ejection fraction, was observed in 6/13 (46%) patients who had received doxorubicin and 2/7 (29%) epirubicin-treated patients. No clinically detectable cardiac toxicity was encountered. The response rate in 25 evaluable patients was 76% (12 CR, 7 PR). Dose intensity was highest in the carboplatin/epirubicin/paclitaxel combination. G-CAT shows high activity and can be administered safely, but only very fit patients are suitable for this regimen as it is associated with considerable toxicity. Carboplatin/epirubicin/paclitaxel was the best tolerated regimen overall.

Natural history of stage IV epithelial ovarian cancer.

PURPOSE: In this report we present the natural history, prognostic factors, and therapeutic implications of stage IV epithelial ovarian cancer (EOC). PATIENTS AND METHODS: We reviewed 192 patients with stage IV EOC as defined in 1985 by the International Federation of Gynecology and Obstetrics. RESULTS: The site of stage IV-defining disease was cytologically positive pleural effusion in 63 patients, liver in 50 patients, lymph nodes in 26 patients, lung in six patients, other sites in 15 patients, and disease at multiple stage IV-defining metastatic sites in 32 patients. Surgery was performed before chemotherapy in 169 patients; 25 patients (14.8%) were left with only microscopic residual disease or less than 2 cm of macroscopic residual disease. The overall response rate to chemotherapy was 56%; the complete response rate was 18%. The median progression-free survival was 7.1 months, and the median overall survival was 13.4 months. The median overall survival of patients with positive pleural effusions only was 13.4 months as compared with 10.5 months for patients with visceral disease only, but this difference was not statistically significant. The 5-year survival rate was 7.6%, with only six patients surviving more than 5 years. Univariate and multivariate analysis showed that two parameters were associated with a shorter survival time: visceral involvement (lung or liver) and diagnosis before 1984. CONCLUSION: Patients with stage IV EOC initially respond to chemotherapy as often as those with less advanced disease, but the long-term prognosis is very poor. The size of residual disease is not a prognostic factor in this group of patients, and, therefore, the role of debulking surgery in these patients needs to be reconsidered.

Prediction of local recurrence of ductal carcinoma in situ of the breast using five histological classifications: a comparative study with long follow-up.

The increased detection of ductal carcinoma in situ (DCIS) by mammographic screening and the more widespread use of breast-conserving surgery have led to a search for histological features associated with the risk of recurrence. In a case control study of 141 patients with long follow-up, we compared the ability of five morphological classifications to predict recurrence after local excision. A significant correlation was not found between recurrence and growth pattern when a traditional classification based on architecture was used nor with necrosis when a scheme based principally on this feature was employed. A correlation was, however, found between recurrence and "differentiation" as defined by nuclear features and cell polarization in a classification recently formulated by the European Pathologists Working Group (EPWG), but this failed to reach statistical significance at the 5% level. A stronger and statistically significant correlation was found between nuclear grade as defined by the EPWG and recurrence when cell polarization was disregarded, using the classification currently employed by the UK National Health Service and European Commission-funded Breast Screening Programmes. This was attributable to a small number of recurring cases being downgraded as a consequence of exhibiting polarized cells. A significant correlation between histology and recurrence was also observed using the Van Nuys classification, which is based on nuclear grade and necrosis. Whether the tumor recurred as in situ or invasive carcinoma was unrelated to histological classification, as was the time course over which it occurred. These findings strongly support the use of nuclear grade to identify cases of DCIS at high risk of recurrence after local excision, but further work is necessary to determine whether nuclear grade or necrosis is more appropriate to subdivide the non-high-grade cases.