The use of high dose d,l-leucovorin in first-line bevacizumab+mFOLFIRI treatment of patients with metastatic colorectal cancer may enhance the antiangiogenic effect of bevacizumab.

The role of d,l-leucovorin (d,l-LV) dose on efficacy and toxicity of first-line bevacizumab+mFOLFIRI or mFOLFIRI treatment has never been investigated in patients with metastatic colorectal cancer. This study was an investigator initiated retrospective observational investigation performed on 450 consecutive patients. The mFOLFIRI regimen consisted of irinotecan (180 mg/m(2)), d,l-LV low (200 mg/m(2)) or high (400 mg/m(2)) dose and bolus 5-fluorouracil (5-FU) (400 mg/m(2)), followed by a 46-h infusion of 5-FU (2400 mg/m(2)). The bevacizumab+mFOLFIRI regimen consisted of bevacizumab (5 mg/kg)+mFOLFIRI. The efficacy (objective response [OR], progression-free [PFS] and overall survival [OS]) and toxicity was evaluated and compared. The use of high versus low dose d,l-LV in bevacizumab+mFOLFIRI regimen improved the OR rate (63 and 38 %, respectively; P = 0.00015), median PFS (13 and 9 months, respectively; P = 0.000005) and median OS (26 and 21 months, respectively; P = 0.0058). The efficacy of mFOLFIRI and the toxicity pattern of both bevacizumab+mFOLFIRI and mFOLFIRI regimens were independent of d,l-LV dose. Beside the d,l-LV dose the bevacizumab-related hypertension was an independent marker of longer survival. The use of high d,l-LV dose in bevacizumab+mFOLFIRI regimen would enhance the antiangiogenic effect of bevacizumab and subsequently the efficacy of treatment without increasing the number of adverse events. These findings need to be further confirmed in a randomized controlled prospective trial.

Cetuximab and platinum-based chemoradio- or chemotherapy of patients with epidermal growth factor receptor expressing adenoid cystic carcinoma: a phase II trial.

BACKGROUND: Epidermal growth factor receptor (EGFR) is highly expressed in adenoid cystic carcinoma (ACC). The efficacy and toxicity of cetuximab with concomitant platinum-based chemoradio- or chemotherapy in patients with locally advanced or metastatic ACC, respectively, was evaluated. METHODS: Eligible patients (9 with locally advanced tumour and 12 with metastases) had positive tumour EGFR expression. The cetuximab loading dose (400 mg m⁻²) was followed by 250 mg m⁻² per week. Locally advanced tumours were irradiated (mean dose 65 Gy) and treated with concomitant cisplatin (75 mg m⁻², intravenously). Patients with metastases received concomitant cisplatin and 5-fluorouracil (4 × 1000 mg m⁻²). RESULTS: For patients with locally advanced disease (median follow-up: 52 months), the median progression-free survival (PFS) was 64 months and the 2-year overall survival (OS) rate was 100%. For patients with metastases (median follow-up: 72 months), the median PFS and OS were 13 and 24 months, respectively. In both groups the objective response rate was >40%. Skin rash, in-field dermatitis, mucositis and vomiting were the most frequent grade 3/4 adverse events. CONCLUSION: In this single-arm study, the efficacy of cetuximab plus chemoradio- or chemotherapy appeared favourable as compared with historical controls. All side effects were manageable and did not hamper the treatment.

Meta- and pooled analyses of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and colorectal cancer: a HuGE-GSEC review.

Worldwide, over 1 million cases of colorectal cancer (CRC) were reported in 2002, with a 50% mortality rate, making CRC the second most common cancer in adults. Certain racial/ethnic populations continue to experience a disproportionate burden of CRC. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been associated with a lower risk of CRC. The authors performed both a meta-analysis (29 studies; 11,936 cases, 18,714 controls) and a pooled analysis (14 studies; 5,068 cases, 7,876 controls) of the C677T MTHFR polymorphism and CRC, with stratification by racial/ethnic population and behavioral risk factors. There were few studies on different racial/ethnic populations. The overall meta-analysis odds ratio for CRC for persons with the TT genotype was 0.83 (95% confidence interval (CI): 0.77, 0.90). An inverse association was observed in whites (odds ratio = 0.83, 95% CI: 0.74, 0.94) and Asians (odds ratio = 0.80, 95% CI: 0.67, 0.96) but not in Latinos or blacks. Similar results were observed for Asians, Latinos, and blacks in the pooled analysis. The inverse association between the MTHFR 677TT polymorphism and CRC was not significantly modified by smoking status or body mass index; however, it was present in regular alcohol users only. The MTHFR 677TT polymorphism seems to be associated with a reduced risk of CRC, but this may not hold true for all populations.

Endocrine mechanism of action of toremifene at the level of the central nervous system in advanced breast cancer patients.

PURPOSE: To differentiate the antagonistic and agonistic effect of toremifene at the level of the hypothalamus-hypophysis axis a leutinizing hormone-releasing hormone (LHRH) test was performed during a phase II clinical trial. METHODS: In 15 postmenopausal patients with advanced breast cancer, follicle-stimulating hormone (FSH) and LH release--induced by an LHRH agonist (Suprefact injection, 0.5 mg s.c.)--was monitored during a 16-week period of toremifene treatment (60 mg/day p.o.). Prolactin, estradiol, and sex hormone-binding globulin (SHBG) levels were also measured. The functional test was carried out prior to toremifene therapy and then 4, 8, 12, and 16 weeks afterward. RESULTS: The drug sensitized the pituitary to the action of the gonadotrophins; the LHRH-induced FSH and LH release showed a considerably increasing tendency during the toremifene therapy. Estradiol levels decreased statistically significantly and SHBG levels showed a statistically significant increase. A decreased level of prolactin is the sign of an antiestrogenic effect of toremifene on the hypophysis and, as a result, provides evidence for a direct influence of toremifene upon the pituitary. An increase in LH and prolactin release in response to the LHRH test was characteristic in the responders. CONCLUSION: According to the LHRH test, the antagonistic effect of toremifene seems to be more dominant than the concomitantly existing agonistic property. Neither clinical nor endocrinological side effects could be observed at the level of the CNS during a prolonged period of toremifene administration.

Influence of hormonal status of patients with cystic disease on the composition of cyst fluid and breast cancer risk.

The relationship between the composition of breast cyst fluid (BCF), the menstrual status and in addition some endocrine events in the history of patients (n = 131) with gross cystic breast disease was investigated. The dehydroepiandrosterone (DHA) levels in type II (K+/Na+ < 1) cysts of the follicular group were significantly higher compared to the type II cysts of the luteal or postmenopausal groups. For testosterone a significant difference existed between the type I (K+/Na+ > or = 1) follicular and type I postmenopausal groups. Estrone levels were significantly higher in type I BCF of patients in the luteal phase compared to both the follicular and postmenopausal type I cysts. Progesterone levels were lowest in the postmenopausal subgroups (both in type I and II cyst). Significant correlations were found between the number of pregnancies and the levels of DHA-sulfate and also progesterone in BCF. DHA levels were correlated with the period of lactation. The K+/Na+ ratios were the lowest in women who lactated for the longest period. The estrone was lowest in BCF of current oral contraceptive (o.c.) users while the estradiol was lowest in patients who had never used o.c. A history of previous o.c. use was associated with a significantly high mean DHA level. A significantly higher DHA and lower testosterone level were demonstrated in BCF of patients who had some previous gynecological interventions. The composition of BCF and the "life of cysts" and thus the rate of breast cancer risk may depend on hormonal status during the menstrual cycles or postmenopause and also on endocrine history of patients.

Characteristics of cystic breast disease with special regard to breast cancer development.

BACKGROUND: This prospective study compares the characteristics of cystic disease of the breast (CDB) of patients who developed breast cancer (BCa) during the follow-up (1.25-4 years) period with those who did not. MATERIALS AND METHODS: K+, Na+, albumin, dehydroepiandrosterone (DHA), DHA-sulphate, oestrone, oestradiol, testosterone and progesterone levels were determined in breast cyst fluid (BCF). Patients presented data about their menstrual status, reproductive history, lactation period, date of first and the number of BCF aspirations, gynaecological interventions, use of oral contraceptives, family history of cancer, smoking habits and coffee consumption. The BCa incidence of patients was compared with the expected number of BCas in an age-matched group of 5143 women. RESULTS: Out of 147 patients 6 developed BCa. The standardized incidence rate was 6.29. There were significant differences in testosterone, oestrone and progesterone levels and also reproductive history of patients who developed BCa compared with patients without BCa. CONCLUSION: The above markers outline a subgroup of patients with the highest BCa risk.

[Hormonal and biochemical characterization of breast cyst fluid in gross cystic mastopathy]. / A nagycisztás mastopathia cisztafolyadékának hormonális és biokémiai jellemzése.

A total of 93 breast cyst fluids (BCF) obtained by needle aspiration of women suffering from gross cystic mastopathy was hormonally investigated. The mean age of the patients was 45 years (range 27-65). Estradiol (E2), progesterone (PROG), testosterone (TE), prolactin (PROL), estriol (E3), dehydroisoandrosterone and its sulfate (DHA, DHA-S) levels were investigated in the BCF and in the respective sera. Tumour marker beta-HCG and CA 15-3 as well as cations (K+, Na+) were determined, too. E2, E3, PROG, TE, PROL, DHA, DHA-S and K+ showed significant accumulation in the BCF compared to the serum values. The K+/Na+ ratio proved to be a useful tool to divide cysts into type I (> or = 1), type II (< 1 but > or = 0.1) and type III (< 0.1) subgroups. In case of type I BCF, higher E2, DHA, DHA-S and PROL levels could be detected, while PROG and TE contents proved to be the highest in type II cysts. These findings indicate that the type I BCF is a marker for "active" GCD of the breast and suggest that it may be associated with increased breast cancer risk. It is suggested therefore when macrocysts are aspirated, sex steroids, steroid hormone precursors and cations in the BCF should be examined routinely, and women with type I cysts should be controlled carefully.

[Steroid hormone receptors in squamous cell carcinoma of the head and neck]. / Szteroidhormon-receptorok vizsgálata fej-nyak laphámrákban szenvedó betegeken.

In this study we have tried to find new prognostic markers to extend the therapeutical modalities for patients with head and neck squamous cell carcinoma. During evolution the development of the pharyngolaryngeal region differs in males and females, therefore this region can be considered as one of the target organs for sex steroids. Some of the tumours, originating from this area, contain hormone receptors that theoretically makes them susceptible for hormone therapy. Therefore the real concentration of steroid receptors is of great clinical importance. We determined the estradiol, progesterone and testosterone receptor content using biochemical method in tumour tissue of 33 male patients with head and neck squamous cell carcinoma. The receptors in the macroscopically intact mucosa in 15 of all tumour cases were also measured. The patients were followed for 18-24 month after operation and postoperative irradiation performed according to the protocol of the Head and Neck Surgery department. There were 26/33 (79%) estradiol receptor positive, 14/33 (42%) progesterone receptor positive and 18/30 (60%) testosterone receptor positive cases among the tumour samples. The healthy mucosa samples were positive in 6/15 (40%), 2/15 (13%) and 3/15 (20%) of cases, respectively. The differences in proportion of positive status between tumour and healthy mucosa was statistically significant. We established that during the control period the highest rate of the tumour-free survival was in the estradiol receptor positive, progesterone receptor negative group. Consequently the steroid receptor status of head and neck squamous cell carcinomas might help in assessing the prognosis of survival, and in possible choice for endocrine treatment, in order to complete the complex tumour therapy.

[Endocrine effect of a new anti-estrogen compound (EGIS-5650, panomifene) in healthy volunteers: phase I/a study]. / Az antisztrogén hatású új vegyület (EGIS-5650, panomifene) endokrin hatásairól egészéges önkénteseken: fázis I/a vizsgálat.

Influence of a new Hungarian antiestrogen, panomifene (PAN) was investigated on some hormone levels of 10 postmenopausal healthy women during a partially double-blind placebo controlled phase I/a study. Following a single oral administration of PAN serum estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin (PROL) levels were measured by RIA at two selected dose levels: 12 mg and 120 mg. The low dose (12 mg) results in an increased E2 level in some cases probably due to the intrinsic estrogenic (agonistic) character of the drug. The high dose (120 mg) seems to have a strong antiestrogenic (antagonistic) action. FSH and LH changed within the normal postmenopausal range at both doses, PROL slightly decreased at 12 mg dose level. During the 14-day follow up, the 120 mg PAN considerably suppressed the PROL secretion proving the antiestrogenic character of the "high" dose. PAN seems to be a safe tamoxifen analogue, the single oral dose of which does not exert any noteworthy (pathogenic) side effect on some hormone levels of healthy women.

Cetuximab, gemcitabine and capecitabine in patients with inoperable biliary tract cancer: a phase 2 study.

PURPOSE: Biliary tract cancer is rare and has dismal prognosis. Chemotherapy has its role in inoperable disease but the role of targeted agents like cetuximab remains to be defined. On the basis of high epidermal growth factor receptor expression of biliary tract cancers this study aims to investigate the efficacy of cetuximab, gemcitabine and capecitabine in an exploratory phase 2 trial. PATIENTS AND METHODS: Inoperable biliary tract cancer patients were treated with the combination of gemcitabine (1000 mg/m(2) on day 1 and 8), capecitabine (1300 mg/m(2)/d on day 1-14) and weekly cetuximab (400mg/m(2) loading and 250 mg/m(2) maintenance dose) in 21-d cycles until progression or the appearance of intolerable side-effects. RESULTS: Out of 34 patients (mean age 59.7 years) accrued in this study 16 had intrahepatic, eight extrahepatic cholangiocarcinoma and 10 gall bladder cancer. The best overall response rate was 17.6% (two complete responses and four partial responses) and the clinical benefit rate was 76.5%. After a median of 15.4 months follow-up the median progression free survival was 34.3 weeks and the median overall survival was 62.8 weeks. The performance status and chemotherapy efficacy were independent and significant markers of survival. Only moderate side-effects were registered in this study. KRAS mutation was evaluable in 24 tumours, all of these were of wild type. CONCLUSION: The efficacy of cetuximab, gemcitabine and capecitabine combination is encouraging and a well tolerated treatment of inoperable biliary tract cancers.

Modulation of oestrone sulphate formation and hydrolysis in breast cancer cells by breast cyst fluid from British and Hungarian women.

Women with gross cystic breast disease may have an increased risk of breast cancer. In this study the ability of breast cyst fluid (BCF), obtained from British or Hungarian women, to modulate oestrone sulphate (E1S) formation or hydrolysis, has been examined. For this, oestrogen receptor-positive (ER+) MCF-7 or MDA-MB-231 (ER-) breast cancer cells were employed. The formation and hydrolysis of E1S was measured using radiometric techniques. BCF from British and Hungarian women mainly inhibited E1S hydrolysis in MCF-7 cells while stimulating hydrolysis in MDA-MB-231 cells. The extent of inhibition or stimulation of E1S hydrolysis in these cells was related to the Na+/K+ ratio of the BCF. There was a significant inverse relationship between the extent to which BCF samples inhibited hydrolysis in MCF-7 cells and stimulated it in MDA-MB-231 cells. BCF stimulated E1S formation in MCF-7 cells while inhibiting formation in MDA-MB-231 cells. No difference in the ability of BCF from British or Hungarian women to inhibit or stimulate E1S hydrolysis was detected in ER+ or ER- breast cancer cells. In contrast, BCF from British women stimulated E1S formation in ER+ cells (median 82%) to a significantly greater extent (P < 0.01) than BCF from Hungarian women (median 33%). The role that E1S has in breast cancer development remains unclear. The greater stimulation of E1S formation by BCF from British women, who have a higher risk of breast cancer than Hungarian women, suggests that it may act as a storage form of oestrogen within cells that can be activated by oestrone sulphatase.