Fernando Arias

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.

microRNA-451 Regulates Macrophage Migration Inhibitory Factor Production and Proliferation of Gastrointestinal Cancer Cells

Purpose: microRNAs (miRNA) are small RNAs that function as post-transcriptional regulators of gene expression. Recent evidence has shown that some miRNAs can act as oncogenes or tumor suppressors. This study was conducted to evaluate the potential association of miRNA expression with clinical outcome in patients with gastric cancer. Experimental Design: Expression of 250 human mature miRNAs was measured by real-time PCR on paraffin-embedded tumor samples of 21 patients with gastric cancer stage III uniformly treated with surgical resection followed by chemoradiation. We identified the miRNAs correlated with disease-free and overall survival times, and the results were evaluated including 24 other patients. In vitro cell proliferation and radiosensitivity studies were done to support clinical data. Results: The results revealed that down-regulation of miR-451 was associated with worse prognosis. miR-451 was detected by in situ hybridization in epithelial cells and showed decreased expression in gastric and colorectal cancer versus nontumoral tissues. Overexpression of miR-451 in gastric and colorectal cancer cells reduced cell proliferation and increased sensitivity to radiotherapy. Microarray and bioinformatic analysis identified the novel oncogene macrophage migration inhibitory factor (MIF) as a potential target of miR-451. In fact, overexpression of miR-451 down-regulated mRNA and protein levels of MIF and decreased expression of reporter genes with MIF target sequences. Moreover, we found a significant inverse correlation between miR-451 and MIF expression in tumoral gastric biopsies. Conclusions: These findings support the role of miR-451 as a regulator of cancer proliferation and open new perspectives for the development of effective therapies for chemoradioresistant cancers.

Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study.

PURPOSE The optimal therapeutic sequence of the adjuvant chemotherapy component of preoperative chemoradiotherapy (CRT) for patients with locally advanced rectal cancer is controversial. Induction chemotherapy before preoperative CRT may be associated with better efficacy and compliance. PATIENTS AND METHODS A total of 108 patients with locally advanced rectal cancer were randomly assigned to arm A-preoperative CRT with capecitabine, oxaliplatin, and concurrent radiation followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)-or arm B-induction CAPOX followed by CRT and surgery. The primary end point was pathologic complete response rate (pCR). Results On an intention-to-treat basis, the pCR for arms A and B were 13.5% (95% CI, 5.6% to 25.8%) and 14.3% (95% CI, 6.4% to 26.2%), respectively. There were no statistically significant differences in other end points, including downstaging, tumor regression, and R0 resection. Overall, chemotherapy treatment exposure was higher in arm B than in arm A for both oxaliplatin (P < .0001) and capecitabine (P < .0001). During CRT, grades 3 to 4 adverse events were similar in both arms but were significantly higher in arm A during postoperative adjuvant CT than with induction CT in arm B. There were three deaths in each arm during the treatment period. CONCLUSION Compared with postoperative adjuvant CAPOX, induction CAPOX before CRT had similar pCR and complete resection rates. It did achieve more favorable compliance and toxicity profiles. On the basis of these findings, a phase III study to definitively test the induction strategy is warranted.

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.

The EORTC cancer outpatient satisfaction with care questionnaire in ambulatory radiotherapy: EORTC OUT-PATSAT35 RT. Validation study for Spanish patients

Objectives: The EORTC OUT‐PATSAT35 RT questionnaire evaluates the satisfaction with care (SC) expressed by cancer outpatients treated with radiotherapy. In this study we assess the psychometric properties of the OUT‐PATSAT35 RT when applied to a sample of Spanish patients.

Quality of life and voice assessment in patients with early‐stage glottic cancer

The purpose of this study was to assess the quality of life (QOL) and voice handicap in a sample of disease‐free patients who had been treated at our center with radiotherapy (RT) or surgery for early glottic cancer.

SPLIT HYPERFRACTIONATED ACCELERATED RADIATION THERAPY AND CONCOMITANT CISPLATIN FOR LOCALLY ADVANCED HEAD AND NECK CARCINOMAS: A PRELIMINARY REPORT

PURPOSE The feasibility and activity of an intensive chemoradiotherapeutic scheme for patients with locally advanced squamous cell head and neck cancers were tested in a single institution Phase II pilot study. METHODS AND MATERIALS Between January 1990 and February 1992, 40 patients were entered into this trial. The treatment protocol consisted of split hyperfractionated accelerated radiation therapy (SHART), 1.6 Gy per fraction given twice per day to a total dose of 64-67.2 Gy for a total of 6 weeks with a 2-week gap, and cisplatin (20 mg/sqm/Days 1 to 5, in continuous perfusion) concomitantly. RESULTS All of the 40 patients are evaluable for response and survival. Toxicity was significant, but tolerable. A complete tumor response to this treatment was achieved by 37 patients (92.5%). With a minimal follow-up of 22 months (median 30 months) there have been 16 local relapses and 19 patients have died, 2 without tumor. The projected 2- and 3-year overall survival rates are 64% (confidence interval (CI) 95%, 49-79%) and 47%, respectively. The 2-year local control probability has been 56% (CI 95%, 39-73%). CONCLUSION This treatment obtains a high rate of complete responses with increased acute toxicity but tolerable late effects. Preliminary results are encouraging for laryngeal neoplasms. A longer follow-up is needed to evaluate the impact of this treatment on patient survival.

Mitomycin, cisplatin, and vindesine followed by radiotherapy combined with cisplatin in stage III nonsmall cell lung cancer: long-term results

PURPOSE To assess the tolerance, response rate, pattern of failure, and long-term survival of patients with unresectable nonsmall cell lung cancer treated with one cycle of induction chemotherapy followed by concurrent cisplatin and radiotherapy. METHODS AND MATERIALS From 1986 to 1988, 45 patients with histologically proven nonsmall cell lung cancer clinical Stage III (29 IIIA and 16 IIIB) were included in this study. Patients received one cycle of Mitomycin C 10 mg/m2 day 1, Cisplatin 120 mg/m2 day 1, and Vindesine 3 mg/m2 days 1, 8, 15, and 22, by i.v. bolus injection. Radiotherapy was started within 4-6 weeks after completion of chemotherapy, with a total tumor dose of 60 Gy, at 2 Gy/day. Cisplatin, 20 mg/m2/day by i.v. continuous infusion was administered for days 1-5 of radiation treatment. RESULTS The main toxic acute effects were nausea-vomiting grade 1-3 in 38 patients (85%). Ten patients (22%) developed esophagitis grade 3. Leukopenia grade 1-2 was observed in 18 patients (40%), grade 3 in 12 (27%), and grade 4 in 4 (9%). Three patients (6.6%) died by granulocytopenia and sepsis. A bronchoscopic proven complete response was achieved in 9 patients (21.5%) and partial response in 28 patients (67%). With a minimum follow-up of 65 months, overall median survival was 13 months, 2-year survival was 21%, and 5-year survival was 7%, with no statistical difference between Stage IIIA and IIIB. Median survival of patients with complete response was 23.2 months, and 5-year survival was 33%. CONCLUSION This treatment scheme produced a severe toxicity and in spite of a high response rate, long-term survival is poor, similar to previous studies with radiotherapy alone.

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.