Comparison between magnetic resonance imaging and rigid rectoscopy in the preoperative identification of intra- and extraperitoneal rectal cancer.

AIM: Accurate preoperative discrimination between extra- and intraperitoneal rectal cancer has important treatment implications. Our main objective was to compare the diagnostic performance of MRI with rigid rectoscopy (RRS) in assessing the location of rectal cancers above or below the peritoneal reflection (PR), using the findings obtained during abdominal surgery for treatment of the cancer as the reference standard. We also compared the accuracy of MRI and RRS in assessing the level of the lower border of the tumour from the anal verge. METHOD: Patients with rectal carcinoma awaiting surgery underwent MRI and RRS. The MRI images were reviewed by two abdominal radiologists who determined the location of the inferior border of the tumour in relation to the PR. Receiver-operating characteristics (ROC) curve analysis was performed to determine the diagnostic performance of RRS at different cut-off values. RESULTS: The sensitivity and specificity were 98.15% and 100%, respectively, for MRI, and 100% and 76.92%, respectively, for RRS at a cut-off value of < 10 cm. The mean level of the lower border of the tumour from the anal verge was 68 ± 44.3 mm on RRS and 73.5 ± 42.4 mm on MRI (P = 0.25), with a trend towards overestimation with MRI. CONCLUSION: RRS is still the main means of assessing the level of a rectal tumour from the anal verge, but MRI has value in determining the level of the tumour in relation to the PR, which cannot be seen on endoscopy.

Plasma estrone sulfate concentrations and genetic variation at the CYP19A1 locus in postmenopausal women with early breast cancer treated with letrozole.

Estrogen synthesis suppression induced by aromatase inhibitors in breast cancer (BC) patients may be affected by single nucleotide polymorphisms (SNPs) of the gene encoding aromatase enzyme, CYP19A1. We assessed the association between plasma estrone sulfate (ES), letrozole treatment, and four SNPs of CYP19A1 gene (rs10046 C>T, rs4646 G>T, rs749292 C>T, rs727479 T>G) which seem to be related to circulating estrogen levels. Patients were enrolled into a prospective, Italian multi-center clinical trial (Gruppo Italiano Mammella, GIM-5) testing the association of CYP19A1 SNPs with the efficacy of letrozole adjuvant therapy, in postmenopausal early BC patients. SNPs were identified from peripheral blood cell DNA. Plasma ES concentrations were evaluated by Radio Immuno Assay. Blood samples were obtained immediately before letrozole therapy (N = 204), at 6-weeks (N = 178), 6 (N = 152) and 12-months (N = 136) during treatment. Medians (IQR) of ES were 160 pg/mL (85-274) at baseline, 35 pg/mL (12-64) at 6-weeks, 29 pg/mL (17-48) at 6 months and 25 pg/mL (8-46) after 12 months treatment. No statistically significant association was evident between polymorphisms and ES circulating levels during letrozole therapy. Letrozole suppression of the aromatase enzyme function is not affected by polymorphisms of CYP19A1 gene in postmenopausal BC patients.

Retreatment with trastuzumab-based therapy after disease progression following lapatinib in HER2-positive metastatic breast cancer.

BACKGROUND: Preclinical data suggest that treatment with lapatinib reinduces sensitivity to trastuzumab in human epidermal growth factor receptor 2(HER2)-positive breast cancer cells. PATIENTS AND METHODS: Between January 2007 and November 2010, 179 HER2-positive metastatic breast cancer patients were treated with lapatinib and capecitabine at nine Italian institutions. We evaluated the clinical outcome of 69 patients (38.5%) retreated with trastuzumab after lapatinib progression. RESULTS: Visceral metastases were identified in 51 (74%) and brain metastases in 16 patients (23%). All patients were pretreated with both trastuzumab- and lapatinib-based therapy. We observed with retreatment with trastuzumab-based therapy: 1 complete remission (2%), 18 partial remission (29%) and 10 stable disease ≥6 months (14%) and 47% of clinical benefit (CB). Median duration of response was 8.1 months [95% confidence interval (CI) 5.5-10.7]. No unexpected toxic effects occurred. At a median follow-up of 13 months, median progression-free survival was 4.9 months (95% CI 4.2-5.6) and overall survival (OS) 19.4 months (95% CI 14.0-25.0). Median OS was longer for patients experiencing CB (not reached versus 13.4 months for patients without CB, P = 0.002). Brain involvement was associated with lower median OS (17.3 versus 23.3 months for patients without brain disease; P = 0.021). CONCLUSION: Retreatment with trastuzumab-based therapy showed CB in 47% of patients progressing during lapatinib-based therapy, leading to a prolonged OS.

Impact of age and gender on the efficacy and safety of upfront therapy with panitumumab plus FOLFOX followed by panitumumab-based maintenance: a pre-specified subgroup analysis of the Valentino study.

BACKGROUND: The safety and efficacy outcome of elderly metastatic colorectal cancer (mCRC) patients fit enough to receive combination chemotherapy plus biological agents is an issue of growing interest. Also, gender-specific differential toxicity and efficacy of anti-epidermal growth factor receptor (EGFR)-based upfront treatments need to be explored. PATIENTS AND METHODS: Valentino was a multicenter, randomized, phase II trial, investigating two panitumumab-based maintenance strategies following first-line panitumumab plus FOLFOX in RAS wild-type mCRC patients. We carried out a subgroup analysis, aimed at assessing the differences in efficacy, safety and quality of life (QoL) according to age (<70 versus ≥70 years) and gender (male versus female). Efficacy endpoints were progression-free survival (PFS), overall survival (OS) and overall response rate (ORR); safety endpoints were rates of any grade and grade 3/4 adverse events (AEs). RESULTS: No significant differences in terms of PFS, OS and ORR were observed between patients aged <70 or ≥70 years and the effect of the maintenance treatment arm on survival outcomes was similar in the two subgroups. The safety profile of both induction and maintenance treatment and the impact on QoL were similar in elderly and younger patients. No significant differences in PFS, OS, ORR or clinical benefit rate were observed according to gender. A significantly higher rate of overall grade 3/4 AEs (P = 0.008) and of grade 3/4 thrombocytopenia (P = 0.017), any grade and grade 3/4 neutropenia (P < 0.0001) and any grade conjunctivitis (P = 0.033) was reported in female as compared to male patients. Conversely, we reported a significantly higher incidence of any grade skin rash (P = 0.0007) and hypomagnesemia (P = 0.029) in male patients. CONCLUSIONS: The upfront choice of an anti-EGFR-based doublet chemotherapy followed by a maintenance strategy represents a valuable option in RAS wild-type mCRC irrespective of gender and age, though a careful evaluation of patients to maximize the risk/benefit ratio is warranted.

Taxane-containing chemotherapy in the treatment of early breast cancer patients.

In primary breast cancer, taxane-based compared with anthracycline-based adjuvant chemotherapy significantly reduces the relative risk of recurrence (ranging from 17% to 36%) and sometimes improves overall survival. Different dosages and schedules of anthracyclines and taxanes have been tested. Randomized studies comparing sequential versus concurrent administrations are in progress and no data about efficacy are available. However, based on a single randomized trial and on indirect comparisons, safety and tolerability seem to be better with sequential schema. A formal comparison between weekly and every 3 weeks administration of taxanes reported no substantial difference in terms of efficacy. However, taking into account a subgroup analysis of this study, and results coming from metastatic disease, the best way to give taxanes seems to be either weekly paclitaxel or docetaxel every 3 weeks. In the majority of the study, taxane efficacy seems to be independent of hormonal receptor status, i.e. active in both hormonal receptor positive and negative disease. In conclusion, taxane-based adjuvant chemotherapy is a standard option for most early breast cancer patients with node-positive disease. No sufficient and dedicated data are available in node-negative disease.

PIK3CA Mutation, Aspirin Use after Diagnosis and Survival of Colorectal Cancer. A Systematic Review and Meta-analysis of Epidemiological Studies.

AIMS: Regular aspirin use has been associated with inhibition of the whole spectrum of colorectal carcinogenesis, including prevention of metastases and reduced total mortality in colorectal cancer. Preclinical data show that aspirin down-regulates PI3 kinase (PI3K) signalling activity through cyclo-oxygenase-2 (COX-2) inhibition, leading to the hypothesis that the effect of aspirin might be different according to PIK3CA mutational status, but epidemiological studies have led to conflicting results. The aim of this study was to assess the relationship between PIK3CA status and the efficacy of regular use of aspirin after diagnosis on overall survival in colorectal cancer patients. MATERIALS AND METHODS: We identified studies that compared post-diagnosis aspirin efficacy in colorectal cancer patients identified by PIK3CA status. Hazard ratios for overall survival were meta-analysed according to PIK3CA status by inverse variance weighting. A pooled test for treatment by PIK3CA status interaction was carried out by weighted linear meta-regression. All statistical tests were two-sided. RESULTS: The overall effect of aspirin was not significant (summary risk estimate = 0.82; 95% confidence interval 0.63-1.08, P = 0.16; I(2) = 57%). In PIK3CA mutant disease (n = 588), aspirin use reduced total mortality by 29% (summary risk estimate = 0.71; 95% confidence interval 0.51-0.99, P = 0.04; I(2) = 0%), whereas in PIK3CA wild-type disease (n = 4001), aspirin use did not reduce overall mortality (summary risk estimate = 0.93; 95% confidence interval 0.61-1.40; P = 0.7; I(2) = 80%) (P interaction = 0.39). There was a beneficial trend for aspirin on cancer-specific survival in PI3KCA mutated subjects (summary risk estimate = 0.37, 95% confidence interval 0.11-1.32, P = 0.1), albeit with high heterogeneity (Q chi-squared = 3.41, P = 0.07, I(2) = 70.7%). CONCLUSION: These findings suggest that the benefit of post-diagnosis aspirin treatment on overall mortality in colorectal cancer may be more marked in PIK3CA mutated tumours, although the low number of studies prevents definitive conclusions. Trials addressing this issue are warranted to assess the efficacy of aspirin in the adjuvant setting.

Prevention of chemotherapy-induced menopause by temporary ovarian suppression with goserelin in young, early breast cancer patients.

BACKGROUND: Standard methods to prevent chemotherapy-induced early menopause in young, breast cancer patients are unavailable to date. Preclinical data has suggested that luteinising hormone-releasing hormone (LH-RH) analogs given during treatment can decrease the gonado-toxicity induced by chemotherapy. This phase II study aimed to assess the activity of such a method in young, breast cancer patients undergoing adjuvant chemotherapy. PATIENTS AND METHODS: Premenopausal patients received the LH-RH analog goserelin 3.6 mg every 4 weeks before and during chemotherapy. According to two-stage optimal phase II Simon design, treatment was considered clinically interesting if it was able to prevent menopause in 19 out of 29 patients of the study population. The resumption of ovarian function was defined by a resumption of menstrual activity or by a follicle-stimulating hormone (FSH) value < or = 40 IU/l within 12 months after the last cycle of chemotherapy. RESULTS: Thirty patients were enrolled and 29 were evaluable. Median age was 38 years (range 29-47). All but one patient received CEF regimen (cyclophosphamide, epirubicin, 5-fluorouracil). Resumption of menstrual activity was observed in 21 patients (72%; 95% CI 52% to 87%) and a FSH value < or = 40 IU/l in 24 patients (83%; 95% CI 63% to 93%). Menses resumption was observed in 16 out of 17 patients (94%) with age <40 years and in five out of 12 patients (42%) with age > or = 40 years. CONCLUSION: Goserelin given before and during chemotherapy may prevent premature menopause in the majority of patients. The different success rate by age, however, indicates the need of a prospective evidence of the efficacy of such a strategy.