Association of CYP1B1 with hypersensitivity induced by taxane therapy in breast cancer patients.

Taxanes represent a group of anticancer drugs with a wide range of activity against breast cancer. Therapy side effects include haematologic toxicity (neutropenia, leucopenia), peripheral neuropathy and hypersensitivity, and demonstrate inter-individual variations. Since it is known that three genes are implicated in taxane turnover, namely ABCB1 in the transport, CYP2C8 in the metabolism and CYP1B1 in the activity, we explored the association among polymorphisms (single nucleotide polymorphisms, SNPs) in these three genes and the occurrence of taxane-induced toxicity. We studied 95 patients affected by breast cancer and under treatment with taxanes as adjuvant, metastatic or neo-adjuvant therapy. We genotyped them for SNPs in the CYP2C8 (alleles *1, *2, *3 and *4), CYP1B1 (alleles *1 and *3) and ABCB1 (1236 C>T; 2677 G>T/A; 3435 C>T) genes by real-time PCR assay. We observed a significant association between the CYP1B1*3 allele and a lower occurrence of hypersensitivity reactions to taxane treatment. We speculate that the highest production of 4-hydroxyestradiol (4-OHE2) metabolite by CYP1B1*3 allele could increase the formation of the 4-OHE2-taxane adduct and possibly inhibit taxane toxicity. We suggest that CYP1B1 might affect taxane hypersensitivity therefore representing, if confirmed in a large cohort of patients, an exploratory hypersensitivity predictive biomarker.

Differences in the availability of new anti-cancer drugs for Italian patients treated in different regions. Results of analysis conducted by the Italian Society Of Medical Oncology (AIOM).

AIMS AND BACKGROUND: Italy is divided into 20 regions. As a consequence of local autonomy, following marketing authorization by the Italian Medicines Agency, each drug for hospital use is not immediately available, because its approval needs to undergo further steps that can be different among regions. The Italian Society of Medical Oncology conducted the present study to describe the impact of the existence of sub-national pharmaceutical formularies on the disparity of access to new anti-cancer drugs among patients treated in different Italian regions. METHODS: The availability of 8 new anti-cancer drugs at a regional level and the coherence of regional authorizations compared with national authorizations approved by the Italian Medicines Agency were analyzed as of April 2009. RESULTS: Fourteen regions and autonomous province of Trento have a regional pharmaceutical formulary. In most cases, the regional pharmaceutical formularies include the eight analyzed drugs, with therapeutic indications coherent with national marketing authorization indications. Five drugs (bevacizumab, trastuzumab, rituximab, erlotinib, sunitinib) were included in all the existing regional pharmaceutical formularies, without restrictions, whereas three drugs (cetuximab, sorafenib, pemetrexed) were found to have restrictions in some regions. CONCLUSIONS: The presence of multiple hierarchical levels of drug evaluation creates a potential element of disparity in the access to pharmacological therapies for Italian citizens.

Impact of intervention aimed at improving the integration of oncology units and local palliative care services: results of the multicentre prospective sequential MIRTO study.

BACKGROUND: Chemotherapy (CT) in patients with advanced cancer (ACP) near the end of life is an increasing practice of oncology units. A closer integration with palliative care (PC) services could reduce the use of potentially harmful CT. This prospective study is aimed at assessing whether a more integrated care model could reduce CT use near the end of life and increase local PC service utilisation. METHODS: The study enrolled sequentially two cohorts of ACP with an estimated life expectancy of ≤6 months. In the first cohort, the usual oncologist's practice to prescribe CT and to activate local PC services were recorded. In cohort 2, the oncologist's decision was taken after an in-hospital consultation with the local PC teams. After patient death, a follow-back survey was carried out. RESULTS: The two cohorts included 109 and 125 evaluable patients, respectively. The oncologist's decision to prescribe CT occurred in 51.4% and 60%, respectively: the percentages of patients receiving the final CT administration in the last 30 days of life did not differ in the two cohorts (33.9% and 29.3%, respectively,p=0.83). Conversely, an increase in home PC service utilisation (from 56.9% to 82.4%, p=0.00), at home deaths (from 40.4% to 56.8%, p=0.01) and in-hospice deaths (from 8.3% to 19.2%, p=0.00) occurred in cohort 2. CONCLUSION: The implementation of an initial in-hospital consultation of oncologists and experienced home PC teams has not reduced the use of CT near the end of life but increased PC service utilisation and reduced in-hospital deaths.

Capecitabine plus oxaliplatin (xelox) versus protracted 5-fluorouracil venous infusion plus oxaliplatin (pvifox) as first-line treatment in advanced colorectal cancer: a GOAM phase II randomised study (FOCA trial).

UNLABELLED: This phase II randomised trial compares oxaliplatin plus protracted infusion of 5-fluorouracil (pviFOX) or oxaliplatin plus capecitabine (XELOX) in the first-line treatment of advanced colorectal cancer (ACRC). METHODS: From December 2001 to March 2005, 118 patients were randomised to arm A (pviFOX: pvi5-FU by a central venous catheter 250 mg/m2/daily d1-21+oxaliplatin 130 mg/m2 d1 q3w) (56 pts) or arm B (XELOX: capecitabine 1000 mg/m2 po bid d1-14+oxaliplatin at the same schedule) (62 pts). RESULTS: Patient characteristics were well-balanced between the two arms. Median number of complete cycles was six. The objective responses were: CR 1 (1.7%) and 3 (4.8%), PR 26 (46.4 %) and 24 (38.7%), SD 13 (23.2%) and 20 (32.3%), P 13(23.2%) and 10 (16.1%), not evaluable 3 (5.4%) and 5 (8.1 %) in arms A and B, respectively; the CR+PR rate was 48.2% (95% confidence limits 34.6%-61.9%) versus 43.5 % (31.0%-56.7%). Median TTP was 7 versus 9 months, respectively. About 50% of the patients with symptoms or low performance status at baseline experienced improvement without major differences between the two arms. G3-4 diarrhoea was observed in 14.0% versus 8.2%, G3 stomatitis in 3.7% versus 0, and G3 neurotoxicity in 18.5% versus 24.6% in arms A and B, respectively. Eight patients in arm A (14.8%) had venous line problems that obliged the temporary suspension (six cases) or stopping (two cases) of the 5-FU infusion. CONCLUSION: Both pviFOX and XELOX are effective and safe first-line treatments for patients with ACRC. By avoiding intravenous (i.v.) administration by a central catheter, XELOX is favoured in clinical practice.

Mesenteric fibromatosis in a patient with Camurati-Engelmann disease. A case report and literature review.

Mesenteric fibromatosis is a rare type of desmoid tumor characterized by local aggressiveness and a tendency to relapse. In view of these characteristics it may be considered a low-grade fibrosarcoma. Camurati-Engelmann disease is a very rare form of bone dysplasia characterized by osteosclerosis of the diaphyses of the long bones. Here we describe the case of a male patient affected by these two rare diseases in association with chronic inflammatory intestinal disease.

Interleukin-2, interferon-alpha and medroxyprogesterone acetate in metastatic renal cell carcinoma.

BACKGROUND: Interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) are the main immuno-biological agents used in the therapy of metastatic renal cell carcinoma (RCC). Unfortunately the promising results obtained in biological studies have not yet been confirmed in clinical studies. One reason is linked to the immunosuppression of metastatic patients which is caused by macrophage products. IL-6 in particular is considered a growth factor for RCC. Medroxyprogesterone acetate (MPA) may interfere with IL-6 macrophage production, possibly causing a synergistic effect in association with IL-2 and IFN-alpha. Therefore the purpose of our study was to evaluate the toxicity and the efficacy of the association between IL-2, IFN-alpha and MPA. PATIENTS AND METHODS: Forty-two consecutive patients with metastatic RCC were enrolled. IL-2 was administered subcutaneously at doses of 4.5 million UI on days 1-5, 8-12, 15-19 and 22-26; IFN-alpha was administered s.c. at a dose of 3 million t.t.w; MPA was administered orally at a dose of 1000 mg daily. This schedule was repeated after a rest of 2 weeks. RESULTS: Toxicity was mild: the main symptoms observed were fatigue and fever. Six CR (14%), five PR (12%), thirteen SD (31%) and seventeen PD (41%) were observed for an overall response rate of 26%. Patients with good PS and low levels of CRP had a better prognosis. CONCLUSION: Considering both the good activity and the low toxicity of this scheme, we think that it could be carried out in normal clinical practice.

[Clinical postoperative surveillance of breast carcinoma]. / Sorveglianza clinica post-operatoria del carcinoma mammario.

The problem of post-surgical clinical follow-up for breast cancer patients is still open. A lot of comparative studies between intensive and minimal follow-up showed no advantage of the former vs. the latter modality. The above data have been confirmed also from sistematic revisions and from pharmaco-economic studies. The ASCO guidelines confirm the importance of clinical surveillance, together with annual mammography and pelvic examination, while no blood tests or other instrumental examinations are indicated in absence of specific symptoms. The follow-up program needs to be realized under the supervision of a specialist with specific experience in the oncologic evaluation. Concerning the patients with high risk of recurrence, there is no agreement, even if no advantage seems to exist with an intensive follow-up program in terms of quality or quantity of life. The Authors suggest that the standard follow-up program should include a thoracic X-ray picture and an abdominal USG, in order to detect early a small number (< or = 2 sites) of visceral metastases, amenable of a treatment. The above program should be realized from a multidisciplinary team (surgeon, medical oncologist, radiotherapist) gaining in terms of quality and sparing time and resources.

Correlation of adverse effects of cisplatin administration in patients affected by solid tumours: a retrospective evaluation.

Cisplatin is the most common antineoplastic drug used for the therapy of solid tumours. To date, researchers have focused on the dosage to be administered for each specific tumour, mainly considering the local adverse effects. The aim of this study was to correlate the severity of the adverse effects with: i) the dosage of cisplatin; ii) the specific site of the tumour; iii) the association with other drugs; and iv) the symptoms. We analysed data from 123 patients with 11 different tumour classes undergoing therapy from 2007 to 2008 at St. Anna Hospital (Ferrara, Italy), using the Spearman non-parametric correlation index. Even though significant correlations were found among the variables, the overall results showed that the main factor influencing the severity of the adverse effects was the dosage of cisplatin administered.

Gastrointestinal stromal tumors and other malignancies: a case series.

PURPOSE: This paper aims to review the clinical and pathological features of gastrointestinal stromal tumors (GISTs) occurring with other malignancies. METHODS: A retrospective analysis has been worked out considering all consecutive patients with GISTs referred to our institution between February 2002 and June 2010. We analyzed the relationship among clinical and biological characteristics of the disease and the occurrence of second cancer. RESULTS: Twenty-four patients with GIST have been recorded: in eight cases (33.3%), a second cancer was diagnosed and was synchronous in six patients. In the subgroup of synchronous malignancy, GISTs (four of stomach and one of ileum) were discovered during surgery for other gastrointestinal cancers, whereas one case (arising in the duodenum) was diagnosed during the staging procedure for another primary cancer. In the subgroup of GISTs associated with a second cancer, median age at diagnosis was higher (69 vs. 65 years), patients were more frequently male (62.5% vs. 43.8%), GISTs were smaller (median size 3 vs. 8 cm), and spindle cell histology was less frequent (25% vs. 69.2%); all cases were CD117-positive. Other characteristics were similar in the two subgroups, with the exception of risk category, with low or very low cases higher (75% vs. 20%), even if not statistically, in the subgroup of cases associated with other cancers. CONCLUSIONS: Because of the limited number of cases, we cannot exclude an incidental relationship, but this association should be considered, especially during disease staging or surgery for other gastrointestinal cancer, when lesions in other intestinal tracts are detected. Larger studies are needed.

Depression and serotonin transporter (5-HTTLPR) polymorphism in breast cancer patients.

BACKGROUND: Mixed evidence in the general population and medically ill patients has suggested that homozygous carriers of the short allele (s/s) of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) may increase the risk of depression in comparison with carriers of the long allele (l/l) or s/l. Given the lack of data in oncology, we examined the relationship of depression with the 5-HTTLPR and psychosocial variables among breast cancer patients. METHODS: A sample of 145 breast cancer patients were studied as regards to depression, psychosocial-related variables (coping, Type D-personality, life events, and social support), and the 5-HTTLPR, which was genotyped by using a standard protocol with DNA extracted from the blood. RESULTS: No difference was found between s/s, s/l and l/l patients on depression and any other psychosocial variable. No gene-by environment (GxE) interactions were observed between the 5-HTTLPR and recent life events. CONCLUSIONS: The study did not provide support of a possible association between 5-HTTLPR polymorphism, alone or in conjunction with life events, and depression in newly diagnosed breast cancer. Further follow-up studies are however necessary to confirm these data.