Jose Juan Illarramendi

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.

Chemoradiotherapy for muscle invading bladder carcinoma. Final report of a single institutional organ-sparing program

PURPOSE Chemoradiotherapy is becoming an alternative to radical cystectomy among patients with muscle invading bladder cancer. We began a prospective study in 1988 to determine the possibilities of conservative treatment and aiming to improve the results obtained by cystectomy alone in invasive bladder cancer. A combination of methotrexate, vinblastine, adriamycin, and cisplatin (M-VAC), followed by radiotherapy and concomitant cisplatin was used. METHODS Fifty patients with good performance status and with stages T2 to T4 operable untreated invasive bladder cancer were entered in the study. Treatment protocol was as follows: (i) cytoreductive transurethral resection; (ii) two cycles of M-VAC chemotherapy; (iii) radiotherapy, 45 Gy on pelvic volume and, at the same time, 20 mg/m(2) cisplatin on days 1 to 5. Cystoscopic evaluation: if there was a complete response, radiotherapy was completed up to 65 Gy; if there was not a complete response, a cystectomy was performed. Median follow-up of the series was 73 months (18-180 m). RESULTS Tumor response was as follows: 34 complete responses (68%), 9 partial responses (18%), and 7 nonresponses (14%) were observed. The 5-year overall survival and local control were 48% and 47%, respectively. For the complete responder patient, 5-year survival and local control were 65% and 70%, respectively. Severe toxicity was uncommon. The most frequent were leucopenia and cystitis. No treatment-related deaths occurred with either treatment protocol. CONCLUSIONS Conservative combination treatment may be an acceptable alternative to immediate cystectomy in selected patients with bladder cancer, although a randomized clinical trial would be required to produce definitive results.

Neoadjuvant chemotherapy and radiotherapy in locally advanced esophagus carcinoma: long-term results.

PURPOSE A prospective study with neoadjuvant chemotherapy and radiotherapy in patients with locally advanced esophagus carcinoma for evaluating: toxicity, response rate, pattern of recurrence, and survival after a long follow-up. METHODS AND MATERIALS Between 1983-1988, 40 patients with locally advanced squamous cell carcinoma of the thoracic esophagus were entered into a prospective trial of neoadjuvant chemotherapy and radiotherapy. Eight patients (20%) were Stage II and 32 patients (80%) were Stage III, according to American Joint Committee staging criteria. Neoadjuvant chemotherapy consisted of two cycles with cisplatin (120 mg/m2 day 1), vindesine (3 mg/m2 days 1, 8, 15, and 22) and bleomycin (10 mg/m2 days 3 to 6). Second cycle was initiated on day 29. Radiation therapy was administered 2-4 weeks after completion of chemotherapy, with a total dose on tumor of 60 Gy. RESULTS Two patients died from treatment-related toxicity. Complete response was observed in 20 patients (53%) and symptomatic improvement in 31 patients (82%). The median survival was 11 months, with an actuarial survival at 1 year of 45%, 3 year 20%, and 5 years 15%. Significantly (p < 0.05) longer survival was observed in patients with Stage II (median survival 18 months) vs. Stage III (median survival 10 months). The pattern of failure was predominantly local/regional (62%). CONCLUSION This treatment scheme is an effective and tolerable regimen but long-term survival was poor.

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.

Hyperfractionated radiotherapy concomitant with cisplatin and granulocyte colony-stimulating factor (filgrastim) for laryngeal carcinoma.

An open-label, non-randomized study evaluated the feasibility and efficacy of filgrastim (recombinant methionyl human granulocyte colony-stimulating factor, r-metHuG-CSF) to prevent mucositis induced by accelerated hyperfractionated radiotherapy (1.6 Gy b.i.d., total dose 67.2 Gy in six weeks with a two-week split) and concomitant chemotherapy (cisplatin, 20 mg/m2/day, days 1-5 by continuous intravenous infusion) in patients with laryngeal carcinoma. Filgrastim 300 microg/day was administered on days 1, 3, and 5 in weeks 2-6 of radiotherapy, after the second fraction. Twenty patients (three stage II, six stage III, and eleven stage IV, according to AJCC) were enrolled in the trial. Oral mucosal toxicity was grade 2 in nine patients (45%), grade 3 in eight (40%), and grade 4 in three (15%). Severe hematological toxicity (WHO criteria) was uncommon. Nineteen patients (95%) completed the treatment in the planned time. Overall survival was 55% at three years. The administration of filgrastim with this regimen was feasible, and it appeared to reduce the severity and duration of mucositis induced by the combined treatment.

CHL1 hypermethylation as a potential biomarker of poor prognosis in breast cancer

The CHL1 gene encodes a cell-adhesion molecule proposed as being a putative tumour-suppressor gene in breast cancer (BC). However, neither the underlying molecular mechanisms nor the clinical value of CHL1 downregulation in BC has been explored. The methylation status of three CpG sites in the CHL1 promoter was analysed by pyrosequencing in neoplastic biopsies from 142 patients with invasive BC and compared with that of non-neoplastic tissues. We found higher CHL1 methylation levels in breast tumours than in non-neoplastic tissues, either from mammoplasties or adjacent-to-tumour, which correlated with lower levels of protein expression in tumours measured by immunohistochemistry. A panel of five BC cell lines was treated with two epigenetic drugs, and restoration of CHL1 expression was observed, indicating in vitro dynamic epigenetic regulation. CHL1 was silenced by shRNA in immortalized but non-neoplastic mammary cells, and enhanced cell proliferation and migration, but not invasion, were found by real-time cell analysis. The prognostic value of CHL1 hypermethylation was assessed by the log-rank test and fitted in a Cox regression model. Importantly, CHL1 hypermethylation was very significantly associated with shorter progression-free survival in our BC patient series, independent of age and stage (p = 0.001). In conclusion, our results indicate that CHL1 is downregulated by hypermethylation and that this epigenetic alteration is an independent prognostic factor in BC.

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.

Quality of life evolution in elderly survivors with localized breast cancer treated with radiotherapy over a three-year follow-up

PURPOSE This paper studies the Quality of Life (QL) of elderly early-stage breast cancer survivors. The aims are to compare the QL scores of these patients after follow-up with their scores before the start of radiotherapy (RT) and compare QL among different axillary treatment groups. METHODS Of 173 patients over 65 who began treatment and completed the EORTC QLQ-C30 and QLQ-BR23 and the Interview for Deterioration in Daily Living Activities in Dementia (IDDD) before RT, 138 also completed these questionnaires three years after RT. Longitudinal changes in QL were assessed for the whole sample using linear mixed-effect models. Also assessed were differences in QL scores between axillary treatment groups (axillary node dissection ALND, sentinel lymph node biopsy SLNB, and no surgery) at the end of the follow-up (Anova or Kruskal-Wallis) and differences in the evolution of QL from baseline among these groups (linear regression models). RESULTS QL scores in the follow-up were high (>70/100 points) in most QL areas, with moderate limitations (>30) in sexual functioning and enjoyment. Five areas (pain, nausea/vomiting, financial impact, breast symptoms and IDDD) improved significantly (<6 points) in the follow-up. The ALND group scored less for the future perspective item (15-20 points) in the follow-up than the other two axillary treatment groups. No differences between the pre-treatment and follow up assessments regarding treatment were found among the axillary treatment groups. CONCLUSIONS Our results suggest that early-stage breast cancer patients adapted well both to their disease and treatments over the follow-up period and to the administration of RT. There were few QL differences between the axillary treatment groups.

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.