Esteban Salgado

Polymorphisms of the Repeated Sequences in the Enhancer Region of the Thymidylate Synthase Gene Promoter May Predict Downstaging After Preoperative Chemoradiation in Rectal Cancer

PURPOSE Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. TS gene promoter possesses regulatory tandemly repeated (TR) sequences that are polymorphic in humans, depending on ethnic factors. These polymorphisms have been reported to influence TS expression. TS expression levels affect tumor downstaging after preoperative fluoruracil (5-FU)-based chemoradiation. Tumor downstaging correlates with improved local control and disease-free survival. The aim of this study is to correlate TR polymorphisms with downstaging and disease-free survival. PATIENTS AND METHODS Sixty-five patients with rectal cancer underwent tumor resection after preoperative 5-FU-based chemoradiation. Tumor downstaging was evaluated by comparing the pretreatment T stage with the pathologic stage observed in the surgical specimen. TS polymorphism genotype was determined by polymerase chain reaction amplification of the corresponding TS promoter region, and products of amplification were electrophoresed, obtaining products of 220 bp (2/2), 248 bp (3/3), or both (2/3). The TS polymorphism genotype results were subsequently compared with the downstaging observed and with disease-free survival. RESULTS Patients who were homozygous for triple TR (3/3) had a lower probability of downstaging than patients who were homozygous with double TR or heterozygous patients (2/2 and 2/3): 22% versus 60% (P =.036; logistic regression). Furthermore, a trend toward improved 3-year disease-free survival was detected in the 2/2 and 2/3 groups, compared with that in the 3/3 group (81% v 41%; P =.17). CONCLUSION This preliminary study suggests that TS repetitive-sequence polymorphisms are predictive for tumor downstaging. TR sequences in TS promoter may be useful as a novel means of predicting response to preoperative 5-FU-based chemoradiation.

Front-Line Paclitaxel/Cisplatin-Based Chemotherapy in Brain Metastases from Non-Small-Cell Lung Cancer

Objective: Paclitaxel-cisplatin is considered to be a standard therapy for metastatic non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the activity and toxicity of this combination with vinorelbine or gemcitabine as front-line therapy in brain metastases from NSCLC. Methods: Twenty-six chemotherapy-naive patients with an ECOG performance status of 0–2 were treated with paclitaxel (135 mg/m2) on day 1, cisplatin (120 mg/m2) on day 1, and either vinorelbine (30 mg/m2) on days 1 and 15 or gemcitabine (800 mg/m2) on days 1 and 8. Whole-brain irradiation was offered early in case of progression and later as consolidation treatment. Results: All patients were evaluated for toxicity and 25 for response. An intracranial response rate was observed in 38% of the patients (95% CI: 22–59%). WHO grade 3–4 neutropenia and thrombocytopenia occurred in 31 and 4% of the patients, respectively. There was one treatment-related death. Non-hematological toxicities were mild. After a median follow-up of 46 months, the median overall survival for all patients was 21.4 weeks and the median time to progression was 12.8 weeks. Conclusions: Paclitaxel and cisplatin combined with vinorelbine or gemcitabine as front-line therapy in brain metastases seem to achieve responses similar to those for extracranial disease, suggesting a meaningful role in this setting.

Intraoperative radiotherapy electron boost followed by moderate doses of external beam radiotherapy in resected soft-tissue sarcoma of the extremities

PURPOSE To analyze the patterns of failure and the toxicity profile of intraoperative electron beam radiotherapy (IOERT) after resection of soft tissue sarcomas of the extremities (STS). PATIENTS AND METHODS Forty-five patients with extremity STS were treated with IOERT and moderate-dose postoperative radiotherapy (45-50 Gy). Twenty-six patients were treated for primary disease (PD) and 19 patients for an isolated recurrence (ILR). Tumor size was >5 cm (maximum diameter) in 36 patients (80%), and high-grade histology in PD patients was present in 14 patients (54%). In nine patients, IOERT was used alone, due to previous irradiation or patient refusal. Chemotherapy (neoadjuvant and/or adjuvant) was mainly given to high-grade tumors. RESULTS Nine patients relapsed in the extremity (20%), and 12 patients in distant sites (28%). Actuarial local control at 5 years was 88% for patients with negative/close margins and 57% for patients presenting positive margins (P=0.04). Five patients (11%) developed neuropathy associated with the treatment. Extremity preservation was achieved in 40 patients (88%). With a median follow-up of 93 months (range: 27-143 months) for the patients at risk, 25 patients remain alive (a 7-year actuarial survival rate of 75% for PD and 47% for ILR; P=0.01). CONCLUSIONS IOERT combined with moderate doses of external beam irradiation yields high local control and extremity preservation rates in resected extremity STS. Peripheral nerves in the IOERT field are dose-limiting structures requiring a dose compromise in the IOERT component to avoid severe neurological damage.

Second-line chemotherapy with irinotecan and vinorelbine in stage IIIB and IV non-small-cell lung cancer: a phase II study.

The purpose of this study was to evaluate the efficacy and tolerance of combined irinotecan and vinorelbine in previously treated patients with stage IIIB and IV non–small-cell lung cancer (NSCLC). Thirty-three patients with NSCLC (7 stage IIIB and 26 stage IV) were enrolled. All had been previously treated with cisplatin, paclitaxel, and gemcitabine as first-line chemotherapy. In addition, 24 patients had received radiotherapy. Irinotecan (300 mg/m2) was administered on day 1 and vinorelbine (30 mg/m2) on days 1 and 14, every 4 weeks. Partial response was achieved in 3 patients (9%; 95% CI: 2–24%), stable disease (SD) in 13 (39%; 95% CI: 23–58%), whereas 17 patients progressed (51%; 95% CI: 33–69%). Median event-free survival was 10 weeks and median overall survival was 25 weeks. Three patients were event free at the end of the study with a follow-up of 40, 73, and 75 weeks. Toxicity was mild, with leukopenia grade III–IV in 8.6% of cycles. No episodes of diarrhea III-IV were observed. Three patients died early after administration of this combination, one of them in the context of severe leukopenia and thrombocytopenia. Approximately 50% of patients treated with CPT-11 and vinorelbine in combination show partial response or stable disease with minimal toxicity.

Determinants of patient satisfaction with care in a Spanish oncology day hospital and its relationship with quality of life.

This study evaluates satisfaction with care (SC) in cancer patients treated at a Spanish day hospital to identify SC determinants and assess the relationship between SC and quality of life.

The cancer outpatient satisfaction with care questionnaire for chemotherapy, OUT-PATSAT35 CT: a validation study for Spanish patients

PurposeThe OUT-PATSAT35 CT questionnaire evaluates satisfaction with care expressed by cancer outpatients receiving chemotherapy. This study assesses the psychometric properties of the OUT-PATSAT35 CT when applied to a sample of Spanish patients.MethodsOne hundred seventy-six patients with different tumour sites and disease stages completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ)-C30, the OUT-PATSAT35 CT, the Oberst patients’ perception of care quality and satisfaction scales (OS) and the item on intention to recommend the hospital (IR). Psychometric evaluation of the structure, reliability and validity of the questionnaire was conducted.ResultsMultitrait scaling analysis showed that 32 of 34 item-scale correlation coefficients met the standards for convergent validity and that many of them met the standards for discriminant validity. Cronbach’s coefficients were good (0.78–0.97) for all scales except doctor availability and environment. Correlations between the QLQ-C30 and the OUT-PATSAT35 CT were low (≤0.40). Correlations between IR and the OUT-PATSAT35 CT were moderate, and correlations between this questionnaire and the OS were fairly low. Areas whose contents were more related had higher correlation coefficients (>0.50) and vice versa (<0.1). Male patients, elderly patients, those with higher education levels, those with higher scores in four OS and patients who had not received surgery showed higher satisfaction with care in several OUT-PATSAT35 CT areas.ConclusionsThe OUT-PATSAT35 CT is a reliable and valid instrument when applied to a sample of Spanish cancer patients. These results are in line with those of the validation study conducted by the authors of the questionnaire and with the validation study for Spain of the OUT-PATSAT35 RT.

An evaluation study of the determinants of future perspective and global Quality of Life in Spanish long-term premenopausal early-stage breast cancer survivors

Aim of the study Quality of life (QL) is important in premenopausal long-term breast cancer survivors. In this study we assessed QL and factors associated with future perspective and global QL in premenopausal early-stage long-term breast cancer survivors from Spain. Material and methods 243 premenopausal stage I-IIIA relapse-free breast cancer patients who had received surgery 5–20 years previously completed EORTC QLQ-C30 and QLQ-BR23 questionnaires once during follow-up. Univariate and multivariate logistic regression analyses were performed. Results QL mean scores were high in most areas (> 80 in functioning; < 20 in symptoms). The main factors for future perspective were emotional and social functioning, fatigue, breast symptom, and body image. The main factors for global QL were fatigue, pain and physical functioning, and emotional and social functioning. The best logistic model to explain future perspective associated high emotional and social functioning and low breast symptoms with a lower risk of low future perspective (R2 = 0.56). Higher scores in physical and emotional functioning and lower scores in fatigue were associated with a lower risk of low global QL (R2 = 0.50). Conclusions Psychological, social, and physical factors were found to be possible determinants of global QL and future perspective. QL in premenopausal early-stage long-term breast cancer survivors may benefit from multidisciplinary treatment.

Retrospective evaluation on safety concerns of adjuvant therapy for elderly breast cancer patients in a clinical setting.

232 Background: Safety concerns have an important role for the decision making of systemic adjuvant therapy in elderly frail breast cancer patients. These patients are not common in controlled clinical trials. METHODS Retrospective observational assessment of major events in a subgroup of elderly (>70 years) breast cancer patients who received adjuvant systemic therapy in a single center (2001-2011). Events were especially evaluated in case of a potential relation to antiestrogen therapy and chemotherapy. RESULTS 176 patients have been evaluated. Median age: 77.5 years (70-94). Median follow-up: 7.3 years (1-12,5). Most patients received hormone therapy with aromatase inhibitors (70 anastrozol, 43 letrozol, 2 exemestane) ot tamoxifen (41 p.). Some patients received adjuvant chemotherapy (41 p.) and trastuzumab (2 p.). Events found in this population included as follows: fractures (19 hip and/or pelvic, 19 arm, 5 leg, 7 vertebral), severe cognitive impairment (27), cardiac failure (23), ocular surgery for cataracts (15), joint and tendon surgery (10), cerebrovascular accidents (9), polymyalgia (4), second neoplasms (1 leukemia, 1 fallopian tube, 2 colon, 1 vulva, 1 uterus, 1 gastric, 1 bladder, 1 maxillary, 1 muultiple myeloma, 1 myelodysplastic syndrome), symptomatic arrythmia (11), cardiac ischemia (4), thromboembolic events (15), neutropenic fever (4) repeated urinary tract infections (9). CONCLUSIONS Events with potential safety concerns are not uncommon in elderly breast cancer patients receiving adjuvant therapy and must be addressed in the treatment plans of these patients.

Abstract P1-13-10: Long-term pathologic findings in the female genital tract after completion of tamoxifen therapy for premenopausal breast cancer

Introduction: Tamoxifen (TMX) remains the main compound for adjuvant hormone therapy in premenopausal breast cancer patients. Potential uterine carcinogenicity and other effects on the female genital tract are recognized risks for TMX, but further studies with longer follow-up are needed for the subpopulation of young premenopausal patients, with prolonged life span. Material and Methods: Retrospective analysis of the female genital tract pathologic findings found in a population of premenopausal breast cancer patients who completed at least five years of adjuvant TMX (20 mg/d) in a single center with a minimum follow-up of 10 years since the start of TMX (1985-June 2003). Periodic gynecologic exams were offered to all the patients and biopsies were performed at the discretion of the reference gynecologists. Pathologic reports from biopsies and surgical specimens were retrieved from the pathology databases of our health system. Menopausal status was defined at diagnosis according to National Comprehensive Cancer Network´s standard criteria. This retrospective study was approved by our local ethics committee. Results: 386 patients (p.) fulfilled inclusion criteria and were searched for data analysis. Median age at the start of TMX: 45 years (23-57). Median follow-up: 14.1 years (10.0-27.5). Further adjuvant hormone therapies were used in 94/386 p. (79 sequential aromatase inhibitors, 15 luteinizing hormone-releasing analogues).11 p. received further adjuvant TMX, mainly within the ATLAS trial, up to 10 years. Hysterectomies during the period of TMX therapy were performed in 24/386 p. Events in the population (all completed the programmed TMX adjuvant therapy) were as follows: 17 locoregional relapses, 37 systemic relapses, 18 contralateral breast cancer, 24 second neoplasms (3 pancreas, 1 endocrine pancreas, 4 melanoma, 4 colon, 3 sarcoma, 2 uterine, 1 ovary, 1 kidney, 1 tongue, 1 thyroid, 1 bladder, 1 lymphoma, 1 leukemia, 1 thyroid). Pathologic findings in the female genital tract after the end of tamoxifen were reported as follows: endometrial and cervical polyps (56), endometrial atrophy (16), endometrial hyperplasia (9), uterine leiomyoma (9), superficial and/or insufficient uterine samples (30), ovarian cysts (9), endometriosis (3), endometritis (1), chronic cervicitis (3), metaplasia (10), adenomyosis (3) vaginal leiomyoma (1), vulvar folliculitis (1), vaginal infiltration from metastatic breast cancer (1), ovarian fibroma (1), ovarian teratoma (1), ovarian metastases from breast cancer (1), vaginal papilloma (1), vaginal polyp (2), vulvar cyst (2),. Endometrial cancer was found in 2/386 p. One of these two patients had a deleterious BRCA2 mutation. Conclusions: The burden of pathologic complications in the female genital tract and endometrial cancer is regarded as low in initially premenopausal breast cancer patients who completed standard adjuvant tamoxifen, even after long follow-up. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-10.

Abstract P4-13-04: Autologous dendritic cells vaccines combined with neoadjuvant chemotherapy increase total pCR in stages II-III non-overexpressing HER2 breast cancer patients and induce phenotypic changes in peripheral blood

Background Based on the synergistic effect between immuno- and chemotherapy (CT), we have elaborated an autologous vaccine with dendritic cells loaded with patients´ own tumor antigens (lysate), and we have already demonstrated that the addition of the vaccines to a standard neoadjuvant CT schedule has increased total pCR (breast+ axilla) in stages II-III non-overexpressing HER2 breast cancer patients (Santisteban M, SABCS 2012). Both cohorts, the control (C) and the vaccinated (V) were well balanced related to demographic characteristics. Toxicity has been similar in both the C and the V cohorts. Moreover, we have analyzed the phenotypic changes in peripheral blood induced by the vaccine and its correlation with pathologic responses. Indeed, we have studied if the amount of lysate used to load the dendritic cells or the total dendritic cell numbers received by the patients in the first five doses (before surgery) is correlated with pCR Methods Twenty-eight patients with stage II-III HER2 negative breast cancer have started on sequential neoadjuvant CT based on dose dense antracyclines (E 100mg/m2 and C 600 mgr/m2) x4 cycles plus GM-CSF followed by taxanes (DOC 75-100 mgr/m2) x4 cycles plus vaccination. The C historic cohort was composed of thirty patients who received the same treatment except for the absence of the vaccines. Vaccine calendar was started after the 4th EC and alternated with DOC and as maintenance up to a maximum of a 2 year-period. The first 5 vaccines were administered before breast surgery. Changes in different lymphocytes populations were measured in peripheral blood of patients at different points by flow cytometry (absolute cell counts). To date, twenty-one patients have both determinations of lymphocyte subpopulations before the 1st and the 6th vaccine. Paired samples t -tests and Fisher exact were used Results pCR was superior in the V cohort (24% versus 3.3%, p = 0.04). Lymphocyte subpopulations were measured in peripheral blood (cells/uL) and a stimulation of the immune system was found after the 5 vaccines schedule at the time of surgery as follows: NK (p<0.001), T cytotoxic CD8 (p = 0.018), T helper CD4 (p = 0.04), CD19 (p = 0.001), HLADRCD8 (p = 0.007), CD16CD8 (p = 0.003), HLADRCD4 (p<0.001), CD16CD4 (p = 0.008) and T regulators lymphocytes (p = 0.004). We did not find any differences among CD57CD8 (p = 0.17), CD56CD8 (p = 0.11), CD57CD4 (p = 0.45) and CD56CD4 (p = 0.65). We neither see correlation among the amount of lysate to load dendritic cells and the tpCR (p = 0.09) nor the amount of dendritic cells (summatory of 5 vaccines) administered intradermally and the pCR (p = 0.59) Conclusions Immunotherapy added to standard neoadjuvant CT could improve total pCR in stage II-III non-overexpressing HER2 breast cancer patients. After 5 doses of vaccination plus chemotherapy, we can observe phenotypic changes in peripheral blood: some immune system subpopulations increased statistically after the treatment in vaccinated patients. Neither the amount of lysate nor the number of dendritic cells used in the five first vaccines significantly correlated with the pRC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-13-04.