Patients and methods: From October 2000 until June 2005, 1121 node-positive patients were randomized to sequential dose-dense epirubicin 110 mg/m² and paclitaxel (Taxol®, Bristol Myers-Squibb, Princeton, New Jersey, USA) 250 mg/m² (group A), or concurrent epirubicin 83 mg/m² and paclitaxel 187 mg/m² (group B), both followed by three cycles of ‘intensified’ combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF). Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments.

Results: Median dose intensity of epirubicin and paclitaxel was double in group A, as designed, with significantly less cycles administered at full dose (P < 0.001). Median cumulative dose of all drugs and total treatment duration, however, were identical between groups. Severe taxane-related toxic effects were more frequent in group A, while severe thrombocytopenia was low and present only in group A. There were no differences in the rates of other hematological toxic effects, including febrile neutropenia. The rates of secondary malignancies were low.

Conclusion: Both regimens as used in the present study are well tolerated and safe. The rates of severe taxane-related toxic effects and thrombocytopenia, although low overall, are significantly increased with the dose-dense sequential regimen.

Materials and methods: Paraffin-embedded tumors from 236 patients, who were randomly assigned to dose-dense conventional chemotherapy with four cycles of E₉₀C₆₀₀ followed by three cycles of C₆₀₀M₄₀F₆₀₀ every 2 weeks (DD) or a rapidly cycled tandem high-dose regimen with two cycles of E₉₀C₆₀₀ every 2 weeks followed by two cycles of E₉₀C₃₀₀₀Thiotepa₄₀₀ every 3 weeks (HD), were available for retrospective central pathological review (116 HD/120 DD). Expression of estrogen receptor (ER), progesterone receptor (PR), MIB-1, epidermal growth factor receptor, and Her-2/neu was evaluated immunohistochemically using tissue microarrays. Results were correlated with follow-up data and treatment effects by proportional hazard Cox regression models (including interaction analysis).

Results: After a median follow-up of 61.7 months, 5-year event-free survival (EFS) as well as overall survival (OS) rates for the 236 patients were significantly better in the HD arm: EFS: 62% versus 41% [hazard ratio (HR) = 0.60, 95% CI 0.43–0.85, P = 0.004]; OS: 76% versus 61% (HR = 0.58, 95% CI 0.39–0.87, P = 0.007). In multivariate analysis, HD, tumor size <3 cm, positive PR, negative MIB-1 staining, and grade 1/2 were associated with favorable outcome. Interaction analysis showed that regarding predictive effects, triple negative (ER/PR/Her-2/neu) and G3 tumors derived most benefit from HD.

Conclusion: Tandem HD improves both EFS and OS in HRBC. This therapy effect may be partly attributable to superior efficacy in the subgroup of triple-negative tumors and/or G3 with their poor prognostic marker profile.

Patients and methods: A total of 35 patients were treated with bortezomib (1.0–1.3 mg/m² on days 1, 4, 8 and 11) and capecitabine (1500–2500 mg/m² on days 1–14) in 3-week intervals for up to eight cycles.

Results: The maximum tolerated doses (MTDs) were bortezomib 1.3 mg/m² and capecitabine 2500 mg/m². The treatment was generally well tolerated and associated with toxic effects that were consistent with the known side-effects of the individual agents. The intent-to-treat overall response rate was 15% and an additional 27% of patients had stable disease (SD). In the 20 patients treated at the MTD, the response rate was 15% and 40% had SD. Median time to progression and overall survival were 3.5 months [95% confidence interval (CI) 1.9–4.4] and 7.5 months (95% CI 5.6–14.6), respectively. Median duration of response was 4.4 months.

Conclusion: The combination of bortezomib and capecitabine is well tolerated and has moderate antitumour activity in heavily pretreated patients.

Patients and methods: An intent-to-treat analysis of all outcomes, before and after unblinding, on the basis of the original randomization was carried out.

Results: In all, 5187 patients were randomly allocated to the study at baseline and, at unblinding, 1579 (66%) of 2383 placebo patients accepted letrozole. At median follow-up of 64 months (range 16–95), 399 recurrences or contralateral breast cancers (CLBCs) (164 letrozole and 235 placebo) occurred. Four-year DFS was 94.3% (letrozole) and 91.4% (placebo) [HR 0.68, 95% confidence interval (CI) 0.55–0.83, P = 0.0001] and showed superiority for letrozole in both node-positive and -negative patients. Corresponding 4-year distant DFS was 96.3% and 94.9% (HR 0.80, 95% CI 0.62–1.03, P = 0.082). Four-year overall survival was 95.1% for both groups. The annual rate of CLBC was 0.28% for letrozole and 0.46% for placebo patients (HR 0.61, 95% CI 0.39–0.97, P = 0.033).

Conclusions: Patients originally randomly assigned to receive letrozole within 3 months of stopping tamoxifen did better than placebo patients in DFS and CLBC, despite 66% of placebo patients taking letrozole after unblinding.

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 (≥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 involvment (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.

Patients and methods: We tested 80 patients for CTC levels before starting a new treatment and after 4, 8 weeks, at the first clinical evaluation and every 2 months thereafter. CTCs were detected using the CellSearch System^TM.

Results: Forty-nine patients had ≥5 CTCs at baseline. At the multivariate analysis, baseline number of CTCs was significantly associated with progression-free survival [hazard ratio (HR) 2.5; 95% confidence interval (CI) 1.2–5.4]. The risk of progression for patients with CTCs ≥5 at last available blood draw was five times the risk of patients with 0–4 CTCs at the same time point (HR 5.3; 95% CI 2.8–10.4). Patients with rising or persistent ≥5 CTCs at last available blood draw showed a statistically significant higher risk of progression with respect to patients with <5 CTCs at both blood draws (HR 6.4; 95% CI 2.8–14.6).

Conclusion: CTCs basal value is a predictive indicator of prognosis and changes in CTC levels during therapy may indicate a clinical response. Testing CTC levels during targeted treatments might substitute other measurement parameters for response evaluation.

Patients and methods: The relationship between body mass index (BMI) and overall survival (OS) and progression-free survival (PFS) in 1067 patients participating in the Scottish Randomised Trial in Ovarian Cancer I trial was assessed. All patients received first-line carboplatin/taxane chemotherapy. The dose of carboplatin was determined by a measured glomerular filtration rate (GFR), ensuring accurate dosing in all categories of BMI and the dose of taxane was not capped. Patients were assigned to one of four categories: underweight (BMI < 18.5), ideal weight (BMI 18.5–24.9), overweight (BMI 25–29.9) or obese (BMI ≥ 30).

Results: There were neither statistically significant differences in PFS or OS between these four groups nor were there any differences in taxane or carboplatin dose intensity. Furthermore, there was no association between BMI and tumour stage or grade at presentation, or completeness of debulking surgery.

Conclusions: Obese patients with epithelial ovarian cancer do not have a poorer prognosis, provided that they receive optimal doses of chemotherapy based on measured GFR and actual body weight.

Patients and methods: From 1990 to 2004, 180 patients with NF-PETs were entered in a prospective database, and predictors of prognosis were tested in uni- and multivariate models.

Results: There were 25 (14%) benign lesions, 38 (21%) neoplasms of uncertain behaviour, 100 well-differentiated carcinomas (56%) and 17 poorly differentiated carcinomas (9%). Radical resection was possible in 93 cases (51.6%). Overall 5-, 10- and 15-year survival rates were 67%, 49.3% and 32.8%, respectively, and were significantly higher in radically resected patients (93%, 80.8% and 65.2%, respectively; P < 0.00001). By multivariate analysis, poor differentiation [hazard ratio (HR) 7.3; P = 0.0001], nodal metastases (HR 3.05; P = 0.02), liver metastases (HR 3.29; P = 0.003), K_i-67 >5% (HR 2.5; P = 0.012) and weight loss (HR 3.06; P = 0.001) were significantly associated with mortality.

Conclusion: This study confirms the good long-term survival of patients with NF-PETs and the prognostic value of WHO classification, liver metastases, poor differentiation, Ki-67, nodal metastases and weight loss. These latter two parameters have a prognostic value similar to that of liver metastases and Ki-67.

Patients and methods: Patients (n = 567) with metastatic colorectal cancer were randomly assigned to receive FLIRI or Lv5FU2-IRI. Primary end point was progression-free survival (PFS).

Results: Patient characteristics were well balanced. PFS did not differ between groups (median 9 months, P = 0.22). Overall survival (OS) was also similar (median 19 months, P = 0.9). Fewer objective responses were seen in the FLIRI group (35% versus 49%, P = 0.001) but the metastatic resection rate did not differ (4% versus 6%, P = 0.3). Grade 3/4 neutropenia (11% versus 5%, P = 0.01) and grade 2 alopecia (18% versus 9%, P = 0.002) were more common in the FLIRI group. The 60-day mortality was 2.4% versus 2.1%.

Conclusions: Irinotecan with the bolus Nordic schedule (FLIRI) is a convenient treatment with PFS and OS comparable to irinotecan with the Lv5FU2 schedule. Neutropenia and alopecia are more prevalent, but both regimens are equally well tolerated.

Patients and methods: Associations between TS, DPD and TP levels, determined by tissue microarrays and immunohistochemistry, and survival was evaluated in 945 CRC patients according to treatment status.

Results: Low TS and DPD expression associated with worse prognosis in stage II [hazard ratio (HR) = 1.69, 95% confidence interval (CI) (1.09–2.63) and HR = 1.92 (95% CI 1.23–2.94), respectively] and stage III CRC patients treated by surgery alone [HR = 1.39 (95% CI 0.92–2.13) and HR = 1.49 (95% CI 1.02–2.17), respectively]. Low TS, DPD and TP associated with trends for better outcome in stage III patients treated with 5-FU [HR = 0.81 (95% CI 0.49–1.33), HR = 0.70 (95% CI 0.42–1.15) and HR = 0.66 (95% CI 0.39–1.12), respectively].

Conclusion: Low TS and DPD expression are prognostic for worse outcome in CRC patients treated by surgery alone, whereas low TS, DPD and TP expression are prognostic for better outcome in patients treated with 5-FU chemotherapy. These results provide indirect evidence that low TS, DPD and TP protein expression are predictive of good response to 5-FU chemotherapy.

Patients and methods: Patients were randomly assigned to receive FOLFIRI: irinotecan (180 mg/m² i.v. on days 1, 15 and 22); FA (200 mg/m² i.v. on days 1, 2, 15, 16, 29 and 30); 5-FU (400 mg/m² i.v. bolus, then 22-h, 600 mg/m² infusion) or CAPIRI: irinotecan (250 mg/m² i.v. infusion on days 1 and 22); capecitabine p.o. (1000 mg/m² b.i.d. on days 1–15 and 22–36). Patients were additionally randomly assigned to receive either placebo or celecoxib (800 mg: 2 x 200 mg b.i.d.).

Results: The trial was closed following eight deaths unrelated to disease progression in the 85 enrolled (629 planned) patients. Response rates were 22% for CAPIRI + C, 48% for CAPIRI + P, 32% for FOLFIRI + C and 46% for FOLFIRI + P. Median PFS and overall survival (OS) times were shorter for CAPIRI versus FOLFIRI (PFS 5.9 versus 9.6 months and OS 14.8 versus 19.9 months) and celecoxib versus placebo (PFS 6.9 versus 7.8 months and OS 18.3 versus 19.9 months).

Conclusion: Due to the small sample size following early termination, no definitive conclusions can be drawn in relation to the noninferiority of CAPIRI compared with FOLFIRI.

We used intravital video microscopy to measure dermal capillary densities in the dorsum of the fingers. Microvascular endothelial function was assessed by laser Doppler flowmetry combined with iontophoresis of pilocarpine (acetylcholine analogue). All measurements were carried out in 18 patients before and after a 6-month treatment with bevacizumab (mean cumulative dose: 3.16 ± 0.90 g).

Mean BP was increased after 6 months of therapy compared with baseline, from 129 ± 13/75 ± 7 mmHg to 145 ± 17/82 ± 7 mmHg for systolic BP and diastolic BP, respectively (P < 0.0001). Compared with the baseline, mean dermal capillary density at 6 months was significantly lower (75 ± 12 versus 83 ± 13/mm²; P < 0.0001), as well as pilocarpine-induced vasodilation (P < 0.05).

Thus, bevacizumab treatment resulted in endothelial dysfunction and capillary rarefaction; both changes are closely associated and could be responsible for the rise in BP observed in most patients.

Patients and methods: Blood samples were collected from 97 patients and 30 healthy volunteers. Quantification of CTCs in 7.5 ml of blood was carried out with the CellSearch System. The results were expressed as number of CTCs/7.5 ml and the cut-off of ≥2 CTCs/7.5 ml was chosen to define the test as positive.

Results: Positive CTCs were detected in 34 of 94 patients (36.2%). Correlation was not found among positive CTCs and location of primary tumor, increased carcinoembryonic antigen level, increased lactate dehydrogenase level or grade of differentiation. Only stage correlated with positive CTCs (20.7% in stage II, 24.1% in stage III and 60.7% in stage IV, P = 0.005).

Conclusions: CTCs detection by CellSearch is a highly reproducible method that correlates with stage but not with other clinical and morphological variables in patients with colorectal cancer. Colon cancer tumor cells are detectable in all stages. Further studies are warranted.

Patients and methods: Patients with locally advanced or metastatic NSCLC, previously treated with platinum-based chemotherapy, were randomly assigned to receive i.v. P500 or P900 every 3 week.

Results: Accrual was terminated with 588/600 patients enrolled because an interim analysis indicated a low probability of improved survival and numerically greater toxicity on the P900 arm. P900 patients were permitted to continue treatment at P500. No statistical difference was observed between the treatment arms (P500 versus P900) for median survival {6.7 versus 6.9 months, hazard ratio [HR] = 1.0132 [95% confidence interval (CI) 0.837–1.226]}, progression-free survival [2.6 versus 2.8 months, HR = 0.9681 (95% CI 0.817–1.147)], or best overall tumor response [7.1% versus 4.3% (P = 0.1616)]. The incidence of drug-related grade 3/4 toxicity was typically <5% on both treatment arms, but was numerically higher on the P900 arm for most toxicity categories.

Conclusions: P900 did not improve any efficacy measure over P500. P500 i.v. every 3 week remains the standard pemetrexed dose for second-line treatment of platinum-pretreated advanced NSCLC.

Patients and methods: Treatment consisted of bortezomib 1.3 mg/m² i.v. twice weekly for two consecutive weeks, followed by a 1-week break. The primary end point was objective response rate (complete response + partial response) by Reponse Evaluation Criteria in Solid Tumors criteria. Secondary end points included safety, toxicity, and progression-free and overall survival.

Results: In all, 25 patients with advanced UC previously treated with combination chemotherapy were enrolled in a multi-institutional single-arm trial from December 2003 through April 2005. Only 29% of patients had node-only metastases. Grade 3/4 drug-related toxic effects included thrombocytopenia (4%), anemia (8%), lymphopenia (8%), sensory neuropathy (6%), hyperglycemia (4%), hypernatremia (4%), fatigue (4%), neuropathic pain (6%), dehydration (4%), and vomiting (4%). No objective responses were observed [95% confidence interval (CI) = 0–12]. The median time to progression was 1.4 months (95% CI = 1.1–2.0 months), and the median survival time was 5.7 months (95% CI = 3.6–8.4 months). There were no treatment-related deaths.

Conclusion: Although bortezomib is well tolerated, it does not have antitumor activity as second-line therapy in UC.

Materials and methods: Patients received 4–8 adriamycin, bleomycin, vinblastine and dacarbazine courses according to stage. Disease was reassessed evaluating late computed tomography scan response improvement (CTRI) and Ga-67 uptake. Patients received no further treatment, radiotherapy (RT) or additional chemotherapy + RT according to the presence of none (low risk), one (intermediate risk) and both parameters (high risk). Patients with bulky mediastinum received RT anyhow.

Results: Among 102 assessable patients, 35 showed late CTRI and 9 residual Ga-67 uptake. In 30 patients with bulky mediastinum, the 3-year progression-free survival (PFS) was significantly better when neither parameter was present (100% versus 69%; P = 0.02). In 72 patients without bulky mediastinum, treatment was tailored according to risk assignment. Relapses occurred in 5 of 47 low-risk and 3 of 21 intermediate-risk patients, with no differences between the two groups, and in 3 of 4 high-risk patients.

Conclusion: This study shows that two on-treatment parameters, late CTRI and residual Ga-67 uptake, can predict PFS in HL and identify patients in which RT can be spared without apparently affecting the outcome.

Patients and methods: Forty-one patients [30 males and 11 females, median age 47 years] consecutively diagnosed with PTCL received three courses of high-dose cyclophosphamide 2000 mg/m²/day, adriamycin 90 mg/m²/day, vincristine and prednisone alternating with three courses of etoposide, cisplatin, cytarabine and prednisone. Responders were submitted to ASCT.

Results: Sixty-eight percent of patients received the planned treatment. After chemotherapy, 20 patients reached complete response (CR), 4 partial response and 17 failed. ASCT was carried out in 17 of 24 candidates due to lack of mobilization (three cases), toxicity (two), early relapse and patient decision (one each). CR rate after treatment was 51%. With a median follow-up of 3.2 years, 5 of 21 CR patients relapsed and 2 died in CR due to secondary neoplasms. Four-year progression-free survival was 30%. Twenty-two patients have died, with a 4-year overall survival of 39%. International Prognostic Index was the main variable predicting survival. No differences were seen among the 24 candidates according to whether or not they underwent ASCT.

Conclusion: This intensive regimen resulted in moderate CR rate, with manageable toxicity in PTCL. The contribution of ASCT in preventing relapse is debatable. Novel strategies to increase CR warrant investigation.

Patients and methods: We carried out a phase II trial (NCT00097929) of oral vorinostat 300 mg b.i.d. (14 days/3 weeks or 3 days/week) in patients with measurable, relapsed DLBCL who had received two or more systemic therapies. Response rate and duration (DOR), time to progression (TTP) and safety were assessed.

Results: Eighteen patients were enrolled (median age: 66 years; median prior therapies: 2). Seven received 300 mg b.i.d. 14 days/3 weeks, but four had grade 3 or 4 toxicity (dose-limiting toxicity, DLT). The schedule was amended to 300 mg b.i.d. 3 days/week), and none had DLT. One achieved a complete response (TtR = 85 days; DOR = >468 days) and one had stable disease (301 days). Sixteen discontinued for progressive disease; median TTP was 44 days. Median number of cycles was 2 (1 to >19). Common drug-related adverse experiences (AEs; mostly grade 1/2) were diarrhea, fatigue, nausea, anemia and vomiting. Three patients had dose reduction; none discontinued for drug-related AEs. Drug-related AE ≥grade 3 included thrombocytopenia (16.7%) and asthenia (11.1%).

Conclusion: Vorinostat was well tolerated at 300 mg b.i.d. 3 days/week or 200 mg b.i.d. 14 days/3 weeks but had limited activity against relapsed DLBCL.

Patients and methods: LDH levels were serially determined in 221 patients with de novo MDS (median age 70 years, range 24–94). The increase in LDH was correlated with survival and acute myeloid leukemia (AML) evolution.

Results: Confirming previous data, an elevated LDH at diagnosis was found to be associated with an increased probability of AML evolution and decreased probability of survival (P < 0.05). In the follow-up, we found that in patients who progressed (to higher IPSS category or AML), LDH levels were significantly higher in the two 3-month period preceding progression compared with the initial two 3-month period (P < 0.005). In a subgroup of patients, the increase in LDH was accompanied or followed by other signs of disease progression, such as occurrence of thrombocytopenia or appearance of circulating blasts. In multivariate analyses, the LDH increase was found to be an independent prognostic variable.

Conclusions: LDH is an interesting follow-up parameter in MDS, which may assist in early recognition of disease progression and thus help in risk stratification and patient selection for interventional therapies.

Patients and methods: M30 and M65 were measured in matched serum and plasma samples from 31 lung cancer patients and 18 controls.

Results: Time allowable between sample acquisition and processing is critical for assays in clinical use. A 4-h delay in processing at room temperature increased M30 (P < 0.0001), an effect minimised by incubation on ice. M30 and M65 in serum were resistant to processing variations including delays. Serum and plasma measurements correlated well although M30 but not M65 was lower in serum (P < 0.0005). Less variation between duplicate assays was observed in serum. Prolonged storage (–80°C) led to increased M30 (12%, 6 months; 34%, 1 year). Sample dilution in the supplied assay diluent proved non-linear, whereas dilution in donor serum or porcine plasma restored linearity up to a ratio of 1 : 6.

Conclusion: We present recommendations that improve the reliability of these assays for clinical use and recommend serum as the preferred matrix with data more resistant to variations in collection.

Patients and methods: The original Whitehall study is a prospective cohort of 17 363 London-based male government employees (age 40–69 years) who were examined in the late 1960s and then followed up for a maximum of 38 years.

Results: Following adjustment for demographic characteristics, risk factors, and prevalent disease, established positive cigarette smoking—cancer gradients were confirmed for carcinoma of the lung, stomach, pancreas, bladder, upper aero-digestive (including oesophagus), and liver, and for myeloid leukaemia. Among the cancers of uncertain relation with smoking, mortality rates for malignancy of the colon, rectum and prostate and for lymphatic leukaemia were elevated in current and/or former smokers. There was essentially no apparent relation between smoking and mortality from carcinoma of the brain or from lymphoma.

Conclusion: In this study, cigarette smoking appears to be a risk factor for several malignancies of previously unclear association with tobacco use.

Patients and methods: We investigated the relation using data from two Italian multicentric case–control studies conducted from 1985 to 2004, including a total of 1115 incident, histologically confirmed cases and 2582 controls hospitalised with acute, non-neoplastic conditions.

Results: Compared with non-drinkers, the multivariate odds ratios (ORs) of RCC were 0.87 [95% confidence interval (CI) 0.73–1.04] for ≤4 drinks per day, 0.76 (95% CI 0.59–0.99) for >4 to ≤8 drinks per day and 0.70 (95% CI 0.50–0.97) for >8 drinks per day of alcoholic beverages, with a significant inverse trend in risk (P value = 0.01). The ORs were 0.85 (95% CI 0.71–1.02) for wine, 0.84 (95% CI 0.68–1.03) for beer and 0.86 (95% CI 0.70–1.05) for spirits consumption, as compared with abstainers. No trend in risk of RCC emerged with duration (P value = 0.94) and age at starting alcohol consumption (P value = 0.81). Results were consistent in men and women, as well as in strata of age, smoking and body mass index.

Conclusions: This pooled analysis found an inverse association between alcohol drinking and RCC. Risks continued to decrease even above eight drinks per day (i.e. >100 g/day) of alcohol intake, with no apparent levelling in risk.

Methods: In 28 European ancestry countries, we quantified changes in breast cancer incidence and mortality using a joinpoint regression analysis from 1960 until last year of available data.

Results: Since 1960, increases in incidence often in the order of 2%–3% per year occurred in all countries, mainly in women 50–69 years old whose incidence in eight countries surpassed the incidence in women 70 years old and more. In 10 countries, a decrease in incidence in women ≥70 years was noticeable in the last years of observation, but the magnitude of this decrease was far from matching the magnitude of the increases observed in the 50–69 age-group. In the beginning of years 2000s, a persistent decrease in mortality of ~2% per year was observed in women 50–69 years old in most countries and parallel declines in mortality were observed in women 70 years or more.

Conclusions: In years 2000s, in a number of countries, the incidence of breast cancer has become greater in middle-aged women than in older women. If trends remain unchanged, the same phenomenon is likely to happen in other countries.