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In the last years, the use of concomitant continuous infusion chemotherapy and radiation therapy has been tested in a variety of solid tumors, with different concentrations and scheduling of drugs; effective improvements in objective responses and survival rates were found in relatively limited clinical experiences, such as advanced cancers of the anus, esophagus, bladder, head and neck, hepatic metastases of gastrointestinal and gynecologic tumors [1]. With regard to soft tissue sarcomas, both in vitro and in vivo studies support the possibility of a synergic activity of Doxorubicin, certainly the most active drug in advanced disease, when administered concomitantly with radiotherapy: Doxorubicin has shown a radiosensitivizing effect [2, 3, 4, 5], while radiotherapy seems to be more effective after Doxorubicin administration [6]. By a clinical point of view, the possibility of obtaining objective responses by using doses lower than those usually necessary with radiotherapy alone or Doxorubicin alone, would lead to a lowering of toxicity, thus improving the therapeutic index and raising the number of eligible patients. In addition, previous studies had shown that when Doxorubicin is given by continuous infusion over 3 to 4 days is less cardiotoxic and as effective as bolus dosing [7, 8, 9].

Rationale: The annual risk of invasive disease in women with breast intraepithelial neoplasia (IEN) is about 8–10 times higher than in the general population, thus IEN can be considered an important target for chemoprevention strategies. The NSABP-P1 trial showed that women with LCIS randomized to tamoxifen at 20 mg/day reduced their risk of invasive breast cancer by 56% (RR=0.44, 0.16–1.06) and women with previous ADH by 86% (RR=0.14, 95% IC, 0.03–0.47). The issue was the increased risk of endometrial cancer and of venous thromboembolism, which significantly limited tamoxifen broad use in a chemoprevention setting. To improve the risk-benefit ratio, the use of lower doses of the drug has been proposed. Recent trials from our group have shown that a dose of 5 mg/day does not increase endometrial proliferation and is associated with a decrease of the estrogenic activity of tamoxifen on IGF-I, SHBG and antithrombin-III, with a potential decrease of venous thromboembolic events. Moreover, tamoxifen exhibits a high tissue distribution, so that a dose of 5 mg/day attains at the breast tissue level a concentration 10 times higher than that needed to inhibit cell growth in vitro. The CYP2D6 enzyme mediates oxidation of N-desmethyl tamoxifen to endoxifen, the most active metabolite of tamoxifen. The SNP CYP2D6*4 (1846G>A) allele accounts for 75% of CYP2D6 poor metabolizer phenotype which have been associated with a higher risk to develop a breast event compared to wild-type (Serrano D et al. Pharmacogenomics J. 2011;11:100–7). Study design and enrollment report: We designed a chemoprevention multicenter randomized double-blind placebo-controlled phase III trial to assess the efficacy and safety of tamoxifen at daily dose of 5 mg or placebo for a total treatment duration time of 3 years, to reduce breast cancer incidence in women with previous IEN (LIN 2–3 and ER-positive or unknown DIN 1b-3). At present in Europe no standard treatment exists to treat these patients, since tamoxifen is not registered for women with prior DCIS (DIN 2–3). With an 80% power and a 1-sided 5% alpha level, we calculated a total sample size of 1400 women to detect a 50% reduction in incidence of breast cancer (Hazard Ratio = 0.5) in the tamoxifen arm. Secondary endpoints are: incidence of other non-invasive breast disorders (i.e., LIN, ductal atypical hyperplasia), endometrial cancer, clinical bone fractures, cardiovascular events, venous thromboembolic events and clinically manifest cataract. We planned also a pharmacogenetic sub-study to assess whether CYP2D6 genotype can explain modulation on surrogate biomarkers of tamoxifen efficacy and safety, such as circulating IGF-I, hormones, mammographic density, endometrial thickness and hot flashes, but also clinical events. As of August 1, 2011, 15 enrolment centers have been activated, n=421 women have been screened and n=166 have been randomized, 181 women refused to participate, 74 women were excluded for ineligibility. Main ineligibility reasons were: ER negative IEN (9 women), cataract (8), previous neoplasms (7), previous use of tamoxifen (6) and age limits (5). Only 1 serious adverse event (venous thrombosis) was registered. No suspected unexpected serious adverse reactions were registered. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A56.

Rationale: Women with breast IEN have an annual risk of invasive disease equal to 8-10 times the general population, thus representing an important target for chemoprevention. In the NSABP-P1 trial, tamoxifen use at 20 mg/day was associated with an 86% reduction of invasive breast cancer in women with previous ADH (RR=0.14, 95% IC, 0.03-0.47) and with a 56% risk reduction in women with previous LCIS (RR=0.44, 0.16-1.06). However, the increased risk of endometrial cancer and of venous thromboembolism, have significantly limited its broad use in chemoprevention. To improve the risk-benefit ratio, the use of lower doses of the drug has been proposed. Recent trials from our group have shown that a dose of 5 mg/day does not increase endometrial proliferation and is associated with a decrease of the estrogenic activity of tamoxifen on IGF-I, SHBG and antithrombin-III, with a potential decrease of venous thromboembolic events. Moreover, tamoxifen exhibits a high tissue distribution, so that a dose of 5 mg/day attains at the breast tissue level a concentration 10 times higher than that needed to inhibit cell growth in vitro. The CYP2D6 enzyme mediates oxidation of N-desmethyl tamoxifen to endoxifen, the most active metabolite of tamoxifen. The SNP CYP2D6*4 (1846G>A) allele accounts for 75% of CYP2D6 poor metabolizer phenotype which have been associated with a higher risk to develop a breast event compared to wildtype (Serrano D et al. Pharmacogenomics J. 2010 Mar 23). Study design and enrollment report: This is a multicenter randomized double-blind placebo-controlled phase III trial with two parallel arms: tamoxifen at daily dose of 5 mg or placebo for a total treatment time of 3 years, to assess the efficacy and the safety of 5 mg/day tamoxifen to reduce breast cancer incidence in women with previous IEN (LIN 2-3 and ER-positive or unknown DIN 1b-3). At present no standard treatment exists to treat these women, particularly in Europe, where tamoxifen is not registered in women with prior DCIS (DIN 2-3). A total of 1400 women will be recruited in 3 years to detect a 50% reduction (Hazard Ratio = 0.5) in the incidence of breast cancer in the tamoxifen arm with an 80% power and a 1-sided 5% alpha level. Secondary endpoints include: incidence of other non-invasive breast disorders (i.e., LIN, ductal atypical hyperplasia), endometrial cancer, clinical bone fractures, cardiovascular events, venous thromboembolic events, and clinically manifest cataract. The pharmacogenetic endpoints include to assess whether CYP2D6 genotype can explain modulation on surrogate biomarkers of tamoxifen efficacy and safety, including circulating IGF-I, hormones, mammographic density, endometrial thickness and hot flashes, but also on clinical events. As of July 27, 2010, 10 enrolment centers have been activated, n=128 women have been screened and n=44 have been randomized. 58 women refused to participate and 26 women were excluded for the following ineligibility reasons: 6 women for use of raloxifene, tamoxifen or other SERMs; 4 women for ER negative primary breast cancer; 3 women for bilateral mastectomy, 2 for previous thromboembolic events, 2 for age limits and 9 for other reasons. No serious adverse events or suspected unexpected serious adverse reactions were registered. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A70.

Seventy-two consecutive patients with disseminated soft tissue sarcoma in the abdomen were prospectively placed in a program of debulking surgery. The tumor was completely resectable in 64% of the patients. Following the first exploration, the median survival was 23 months for those with resection of metastases and 9 months for those without resection (p less than or equal to 0.01); the former group had a survival rate of 28% at 3 years, 18% at 4 years, and 4% at 5 years (44%, 37%, and 10%, respectively, for low-grade sarcomas, i.e., grade I or II sarcomas), whereas in the latter group, none survived for 3 years. In the group with resection, patients with grade III tumors had a median survival longer by 6 months, and those with low-grade tumors by 28 months (p less than or equal to 0.001), over the respective median survival of patients with unresectable tumors. Metastasectomy appeared to prolong survival in all patients and significantly so in patients with low-grade tumors and those with long disease-free intervals.

Patients presenting with clinical features of locally advanced, non-metastatic breast cancer (T3–T4, N2–N3, M0) have a poor prognosis. After loco-regional treatment by radiation therapy and/or surgery the recurrence rate is high and rapid with median survival less than three years [1–3]. Although not evaluated in randomized clinical trials, there is evidence that the combination of local and systemic treatment has produced a substantial improvement, as compared to historical controls. Five-year survivals in excess of 50 % have been reported from studies in which chemotherapy is used before and after local treatment [4]. In the present report, we review our experience with a multidisciplinary therapeutic approach in patients with locally advanced breast cancer; moreover we have analyzed the relevance of some pretreatment and treatment-related variables in affecting the results in terms of disease-free survival and overall survival.

From May 1985 to June 1992, 375 patients (pts) were enrolled in a prospective controlled randomized clinical trial of periop adjuvant chemotherapy (PAC) associated to long-term adjuvant chemoendocrinotherapy in order to test the effectiveness of reducing the time interval between surgery and chemotherapy. Here, the short-term surgical complications related to PAC are reported in order to verify whether such treatment might negatively affect the results of breast cancer surgery. Pts undergoing PAC received with in 48–72 hour following surgery one course of CY (600 mg/sqm), EPI (60 mg/sqm), and 5-FU (600 mg/sqm) (CEF): pN+ pts, who were given perioperative CEF, had five further cycles of CEF alternated with six cycles of CMF (CY 600 mg/sqm, MTX 40 mg/sqm, 5-FU 600 mg/sqm). All other pN+ pts had six cycles of CEF alternated with six cycles of CMF, starting with in 30 days after surgery. No significant difference of postop morbidity was observed in the two groups as regards median hospital stay (8 days), number of out patient dressings (3.5 vs 3), seroma (51 = 26.9% vs 45 = 24.2%), lymphatic drainage (400 vs 409 ml), and postop infections, both local (10 vs 9) and in extraop foci (6 vs 7). The toxicity of the periop CEF was mainly gastrointestinal (nausea and vomiting 55%, stomatitis 3%), with only a small percentage (9%) reaching grade III–IV.

Estrogen (ER) and progesterone (PgR) receptors were evaluated in the tumor tissue (T) and in the mammary gland far from malignancy (D) in 36 breast cancers. Results were correlated with the pathological grading of the tumor and the axillary nodal status. It is suggested that a lower cancer malignancy with negative nodes and lower values of pathological grading (G1-G2) may be associated with a high level of ER in the mammary parenchyma far from the tumor (D).

In a patient with recurrent head and neck squamous cell carcinoma, reconstruction of the floor of the mouth was carried out by transposition of a pectoralis major myocutaneous flap after composite resection. Twelve months after surgery, a chest wall metastasis corresponding to the site of the vascular pedicle was observed. It appears that the lymphatic and hematogenous tumor spread can occur along the vascular pathways of a transposed myocutaneous flap.

Thirty-nine patients with locally advanced breast cancer (T3b-4, N1-3 or inflammatory carcinoma) received 3 cycles of induction chemotherapy with estrogenic recruitment before surgery. The therapeutic regimen consisted of diethylstilbestrol (DES) orally on days 1-3, 5-Fluorouracil + Doxorubicin + Cyclophosphamide on day 4 q 21 days (DES-FAC). After surgery 6 additional cycles of chemotherapy (3 DES-FAC alternating with 3 DES-CMF with Methotrexate + F and C as in FAC) were administered. The objective response rate was 71.8% with 15.4% CR, and 56.4% PR; after surgery 36/39 (92.3%) patients were rendered disease-free. So far, 13 of 26 patients in stage IIIb have relapsed (9 of 13 with inflammatory carcinomas). Three-year survival and progression-free survival are 60% and 53.5%, respectively. Twenty-three of the 39 patients were subjected to serial tumor biopsies during the first DES-FAC regimen to allow for tumor-cell kinetic studies during DES and chemotherapy. A significant estrogenic recruitment occurred in 16 patients (69.6%), irrespective of estrogen-receptor status. At surgery, 3-4 weeks after induction chemotherapy, tumor proliferative activity was significantly depressed in comparison to basal values. These results indicate that breast cancer cells can be recruited in vivo with DES and that chemotherapy following estrogenic stimulation is effective and feasible with acceptable toxicity.

From 1976 to 1985, 61 consecutive patients with locally advanced breast cancer were treated with multimodality therapy. Overall 5-year survival was 30% with a median survival of 36 months. 50% of patients relapsed within 13 months. Other factors such as menopausal status, side of illness (right or left breast), responses to systemic or to local treatment, survival and progression-free survival in responders and non-responders have been analyzed.

TPS1610 Background: Breast IntraEpithelial Neoplasia (IEN) is associated with a 8-10 fold increased risk of invasive disease, thus representing an important target for chemoprevention. The NSABP-P1 trial showed that tamoxifen (TAM) at 20 mg/day is associated with a 86% reduction of invasive breast cancer (BC) in women with previous atypical ductal hyperplasia (ADH) (RR=0.14, 95% IC, 0.03-0.47) and with a 56% risk reduction in women with previous LCIS (RR=0.44, 0.16-1.06). However, TAM broad use in chemoprevention has been significantly hampered by the increased risk of endometrial cancer and of venous thromboembolism (VTE). We recently showed that a dose of 5 mg/day does not increase endometrial proliferation, is associated with a decrease of the estrogenic activity of TAM on IGF-I, SHBG and antithrombin-III, and attains at the breast tissue level a concentration 10 times higher than that needed to inhibit cell growth in vitro. The CYP2D6 enzyme mediates oxidation of N-desmethyl tamoxifen to endoxifen, the most active metabolite of TAM. The SNP CYP2D6*4 (1846G>A) allele accounts for 75% of poor metabolizer phenotype which have been associated with a higher risk of a breast event compared to wildtype (Pharmacogenomics J. 2011;11:100-7). Methods: A randomized double-blind placebo-controlled phase III trial to assess the efficacy and safety of 5 mg/day TAM vs. placebo for 3 years in women with previous IEN (LIN 2-3 and ER+ or unknown DIN 1b-3). In Europe TAM is not registered in women with prior DCIS. 1400 women are needed to detect 50% reduction in the incidence of BC in the TAM arm (80% power, 1-sided 5% α error). Secondary endpoints are: incidence of other non-invasive breast disorders, endometrial cancer, clinical bone fractures, cardiovascular events, VTE events, and clinically manifest cataract. Pharmacogenetic endpoints includes the association between CYP2D6 genotype and modulation of biomarkers of TAM efficacy and safety (circulating IGF-I, hormones, mammographic density, endometrial thickness and hot flashes) and clinical events. As of February 5, 2013, 18 enrolment centers have been activated and n=338 women have been randomized. No suspected unexpected serious adverse reactions were registered. Clinical trial information: NCT01357772.

Background: The timing of adjuvant chemotherapy and tamoxifen (TAM) has been investigated only in postmenopausal women with breast cancer. We analyzed the outcome of both pre- and postmenopausal women who entered two randomized trials (Gruppo Oncologico Nord-Ovest-Mammella Intergruppo studies) on adjuvant chemotherapy and received either concomitant or sequential TAM. Patients and methods: Patients who received anthracycline-based regimens and either concomitant or sequential TAM were eligible. The primary end point was overall survival (OS). Hazard ratios (HRs) of death or recurrence for treatment comparisons were estimated by Cox proportional hazards regression models. Results: Among the 1096 eligible patients, 507 (46.3%) and 589 (53.7%) received concomitant and sequential TAM, respectively. The median follow-up time was 6.6 years. Ten-year OS was 83% [95% confidence interval (CI) 78–88%] and 80% (95% CI 74–86%) in the concomitant and sequential groups, respectively. Multivariate analyses confirmed no significant difference in the hazard of death (HR = 1.13; 95% CI 0.78–1.64; P = 0.534) and recurrence (HR = 1.03; 95% CI 0.80–1.33; P = 0.88) between the two groups. A decreasing trend (P = 0.015) in HR of death with increasing age was observed indicating, that concomitant therapy might be more effective than sequential therapy in young patients. Conclusions: We observed no outcome difference between sequential and concomitant chemo-endocrine therapy. The potential advantage of concomitant TAM in young patients needs to be further addressed in prospective trials.

PURPOSE Although erythropoietin (EPO) is known to be useful in treating chemotherapy-induced anemia, few data are available on its potential preventive role. The aim of this study was to evaluate the ability of EPO in preventing the development of clinically significant anemia in patients treated with chemotherapy. PATIENTS AND METHODS Sixty-two early-stage breast cancer patients undergoing accelerated adjuvant chemotherapy were randomized to receive EPO 150 U/kg three times a week or no additional treatment. Chemotherapy consisted of six cycles of cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2 (CEF) intravenously on day 1, every 2 weeks with the support of granulocyte colony-stimulating factor (G-CSF), 5 microg/kg subcutaneously from day 4 to day 11. RESULTS Throughout the six cycles of chemotherapy, EPO-treated patients maintained stable values of hemoglobin, whereas control patients developed a progressive anemia. At the end of chemotherapy, the mean (+/- SD) hemoglobin decrease in the control group was 3.05 g/dL (+/- 1.0; 95% confidence interval [CI], 2.6 to 3.5), whereas in the EPO group it was 0.8 (+/- 1.4; 95% CI, 0.3 to 1.4). Clinically significant anemia (hemoglobin < or = 10 g/dL) occurred in 16 patients (52%; 95% CI, 33 to 69) in the control arm and in no patient (0%; 95% CI, 0 to 14) in the EPO arm (P = .00001). CONCLUSION EPO prevents anemia in patients undergoing chemotherapy. Further trials are required to identify subsets of patients in which the preventive use of this drug could be cost-effective.