Determining the optimal interval between neoadjuvant radiochemotherapy and surgery in rectal cancer: a retrospective cohort study.

INTRODUCTION: In locally advanced rectal cancer, the optimal interval between completion of neoadjuvant radiochemotherapy (RT-ChT) and surgical resection remains unclear due to contradictory data on the benefits of extending this interval. Therefore, the aim of this retrospective study was to determine the impact of this interval on outcomes in patients treated for rectal cancer at our center. METHODS: We retrospectively reviewed 382 consecutive patients treated for stage II/III rectal cancer between October 1, 2012, and December 31, 2017. We evaluated four different cut-off points (56, 63, 70, and 77 days) to determine which had the greatest impact on treatment outcomes. RESULTS: The median time between completion of RT-ChT and surgery was 67.2 days (range, 28-294). Intervals > 8 weeks (56 days) were associated with worse therapeutic outcomes. Specifically, an interval ≥ 77 days was associated with a significant decrease in overall survival (OS; 84% vs. 70%; p = 0.004), which is why we selected this interval for the comparative analysis. Several outcome variables were significantly better in the short interval (< 77 days) group, including margin involvement (5.2% vs. 13.9%; p = 0.01), sphincter preservation (78% vs. 59.3%; p = 0.003), and distant dissemination (22.6% vs. 32.5%; p = 0.04). No significant between-group differences were found in complete/nearly complete response rates (19.2% vs. 24.4%; p = 0.3). Time to surgery was statistically significant on both the univariate and multivariate analyses. CONCLUSIONS: Our findings suggest that surgery should not be delayed more than 8 weeks (56 days) after neoadjuvant treatment. An interval > 8 weeks should only be considered in patients who demonstrate a good response to neoadjuvant RT-ChT.

Short-Course Radiotherapy in Locally Advanced Rectal Cancer.

INTRODUCTION: To date, we do not know the best therapeutic scheme in locally advanced rectal cancer when patients are older or have comorbidities. METHODS: In 2009, we established a prospective treatment protocol that included short-course preoperative radiotherapy (RT) with standard surgery +/- chemotherapy in frail patients, mostly older than 80 years or with comorbidities. RESULTS: We included 87 patients; the mean follow-up was 43.5 months (0.66-106.3). Disease-specific survival and disease-free survival at 36 months were 86.3% and 82.8%; at 60 months, they were 78.2% and 78%, respectively, with a local recurrence rate of 2.5%. The rate of late radiotoxicity was 9% in the form of sacral insufficiency fracture and small bowel obstruction with one death. The interval before surgery varied according to the involvement of the mesorectal fascia, but it was less than 2 weeks in 45% of cases. The rate of R0 was 95%. Surgical complications included abdominal wound dehiscence (3.5%), anastomotic leak (2.4%), and reoperations (11.5%). Downstaging was observed in 51% of the cases, regardless of the interval before surgery. DISCUSSION: Therapeutic outcomes in our group of elderly patients and/or patients with comorbidities with neoadjuvant short-course RT are such as those of the general population treated with neoadjuvant RT-chemotherapy, all with acceptable toxicity. Therefore, this treatment scheme, with short-course preoperative RT, would be the most appropriate in this group of patients.

Outcomes after neoadjuvant treatment with gemcitabine and erlotinib followed by gemcitabine-erlotinib and radiotherapy for resectable pancreatic cancer (GEMCAD 10-03 trial).

BACKGROUND: Neoadjuvant therapy (NAT) for pancreatic adenocarcinoma (PDAC) patients has shown promising results in non-randomized trials. This is a multi-institutional phase II trial of NAT in resectable PDAC patients. METHODS: Patients with confirmed resectable PDAC after agreement by two expert radiologists were eligible. Patients received three cycles of GEM (1000 mg/m2/week) plus daily erlotinib (ERL) (100 mg/day). After re-staging, patients without progressive disease underwent 5 weeks of therapy with GEM (300 mg/m2/week), ERL 100 mg/day and concomitant radiotherapy (45 Gy). Efficacy was assessed using tumor regression grade (TRG) and resection margin status. Using a single-arm Simon's design, considering the therapy not useful if R0 < 40% and useful if the R0 > 70% (alpha 5%, beta 10%), 24 patients needed to be recruited. This trial was registered at ClinicalTrials.gov, number NCT01389440. RESULTS: Twenty-five patients were enrolled. Adverse effects of NAT were mainly mild gastrointestinal disorders. Resectability rate was 76%, with a R0 rate of 63.1% among the resected patients. Median overall survival (OS) and disease-free survival (DFS) were 23.8 (95% CI 11.4-36.2) and 12.8 months (95% CI 8.6-17.1), respectively. R0 resection patients had better median OS, compared with patients with R1 resection or not resected (65.5 months vs. 15.5 months, p = 0.01). N0 rate among the resected patients was 63.1%, and showed a longer median OS (65.5 vs. 15.2 months, p = 0.009). CONCLUSION: The results of this study confirm promising oncologic results with NAT for patients with resectable PDAC. Therefore, the present trial supports the development of phase II randomized trials comparing NAT vs. upfront surgery in resectable pancreatic cancer.

Initial Experience in the Treatment of "Borderline Resectable" Pancreatic Adenocarcinoma. / Experiencia inicial en el tratamiento del adenocarcinoma de páncreas borderline resectable.

INTRODUCTION: A borderline resectable group (APBR) has recently been defined in adenocarcinoma of the pancreas. The objective of the study is to evaluate the results in the surgical treatment after neoadjuvancy of the APBR. METHOD: Between 2010 and 2014, we included patients with APBR in a neoadjuvant and surgery protocol, staged by multidetector computed tomography (MDCT). Treatment with chemotherapy was based on gemcitabine and oxaliplatin. Subsequently, MDCT was performed to rule out progression, and 5-FU infusion and concomitant radiotherapy were given. MDCT and resection were performed in absence of progression. A descriptive statistical study was performed, dividing the series into: surgery group (GR group) and progression group (PROG group). RESULTS: We indicated neoadjuvant treatment to 22 patients, 11 of them were operated, 9 pancreatoduodenectomies, and 2 distal pancreatectomies. Of the 11 patients, 7 required some type of vascular resection; 5 venous resections, one arterial and one both. No postoperative mortality was recorded, 7 (63%) had any complications, and 4 were reoperated. The median postoperative stay was 17 (7-75) days. The pathological study showed complete response (ypT0) in 27%, and free microscopic margins (R0) in 63%. At study clossure, all patients had died, with a median actuarial survival of 13 months (9,6-16,3). The median actuarial survival of the GR group was higher than the PROG group (25 vs. 9 months; p < 0.0001). CONCLUSION: The neoadjuvant treatment of APBR allows us to select a group of patients in whom resection achieves a longer survival to the group in which progression is observed. Post-adjuvant pancreatic resection requires vascular resection in most cases.

Results of surgery for pelvic recurrence of rectal cancer. Experience in a referral center. / Resultados de la cirugía de la recidiva pélvica de cáncer de recto. Experiencia en un centro de referencia.

INTRODUCTION: The only curative treatment of pelvic recurrence of rectal cancer is radical resection. The aim of this paper is to analyze our experience in surgery for local recurrence of rectal cancer. METHODS: We performed a descriptive retrospective analysis of patients treated with curative intent for local recurrence of rectal cancer from May 2000 to January 2014. The presence of resectable liver or lung metastases was not an exclusion criterion. The descriptive results, overall survival and disease free survival are presented. RESULTS: A total of 35 patients were included. In 18 patients an abdomino-perineal resection of the remaining rectum was performed. Two of them included excision of lower sacral vertebrae, while in 17 patients, sphincter sparing surgery was performed. The most frequent postoperative complications were pelvic collection and postoperative ileus. Seven patients required reoperation and one patient died. Overall survival at one year was 91.2%, at 2 years 75.6% and at 5 years 37%. CONCLUSIONS: Local recurrence of rectal cancer is a disease with high curability rate. The only curative option is radical surgery, with acceptable mortality.

Phase II study of preoperative bevacizumab, capecitabine and radiotherapy for resectable locally-advanced rectal cancer.

BACKGROUND: To evaluate whether the addition of bevacizumab (BVZ) to capecitabine-based chemoradiotherapy in the preoperative treatment of locally advanced rectal cancer (LARC) improves efficacy measured by the pathological complete response (pCR) rate. METHODS: A phase II two-step design was performed. Patients received four cycles of therapy consisting of: BVZ 10 mg/kg in first infusion on day 1 and 5 mg/kg on days 15, 29, 43, capecitabine 1800 mg/m(2)/day 5 days per week during radiotherapy, which consisted of external-beam irradiation (45 Gy in 1.8 Gy dose per session over 5 sessions/week for 5 weeks). Six to eight weeks after completion of all therapies surgery was undergone. To profile the biological behaviour during BVZ treatment we measured molecular biomarkers before treatment, during BVZ monotherapy, and during and after combination therapy. Microvessel density (MVD) was measured after surgery. RESULTS: Forty-three patients were assessed and 41 were included in the study. Three patients achieved a pathological complete response (3/40: 7.5%) and 27 (67.5%) had a pathological partial response, (overall pathological response rate of 75%). A further 8 patients (20%) had stable disease, giving a disease control rate of 95%. Downstaging occurred in 31 (31/40: 77.5%) of the patients evaluated. This treatment resulted in an actuarial 4-year disease-free and overall survival of 85.4 and 92.7% respectively. BVZ with chemoradiotherapy showed acceptable toxicity. No correlations were observed between biomarker results and efficacy variables. CONCLUSION: BVZ with capecitabine and radiotherapy seem safe and active and produce promising survival results in LARC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00847119 . Trial registration date: February 18, 2009.

Interobserver variability in target volume delineation in postoperative radiochemotherapy for gastric cancer. A pilot prospective study.

INTRODUCTION: The aim of this study is to determine the interobserver variability (IV) between radiation oncologists (RO) in target volume delineation for postoperative gastric cancer (GC) radiotherapy planning. MATERIALS AND METHODS: Four physicians were asked to delimitate clinical target volume (CTV) on the same 3D CT images in 9 postoperative radiochemotherapy GC patients. Instructions were given to include tumour bed, remaining stomach, anastomosis, duodenal loop and local lymph nodes. The principal variable was spatial volume discrepancy between the main observer (called "A") and other observers (all called "B"), which were compared using the mathematical formula A⌣B/A⌢B, applied to the 3D CT images using Boolean operators. Analysis of variance with two random effects (observers and patients) was performed. RESULTS: Mean volumes were 1410 cm(3) for OBA, 1231 cm(3) for OB2, 734.6 cm(3) for OB3 and 1350 cm(3) for OB4. Discrepancies were 519.9±431.6 cm(3) for OB2, 652.1±294.36 cm(3) for OB3 and 225.90±237.07 cm(3) for OB4. Standard deviation ascribed to patients as random effect was 898.6 cm(3) and that ascribed to observers was 198.10 cm(3), considered as a statistically significant difference. CONCLUSIONS: A significant IV in target delineation that can be attributed to many factors depends more on patients' characteristics than RO delineating decisions.

Twenty-year experience in the management of squamous cell anal canal carcinoma with interstitial brachytherapy.

OBJECTIVES: The aim of this study was to retrospectively evaluate clinical characteristics, local control, acute and late toxicity, and prognostic factors of patients with anal canal carcinoma treated with brachytherapy. METHODS: From 1989 to 2009, 38 patients were treated with iridium 192 low-dose-rate (N = 26) or pulsed-dose-rate (N = 12) interstitial brachytherapy at a single institution. The median age was 62 years (range, 38-86 years). The TNM classification was as follows: 10 T1, 22 T2, 5 T3 and 1 T4; 32 N0, 3 N1 and 3 N2. Most patients (32/38) received either a first course of radiochemotherapy (N = 22) or radiotherapy alone (N=10) consisting of a total delivered dose of 45 Gy to the pelvis (range, 32-50) followed by a boost a median of 18 days later of 15-35 Gy (median 20 Gy) to the anal canal. The remaining 6 cases were treated with brachytherapy alone (dose range, 60-65 Gy). RESULTS: With a median follow-up of 30 months (range, 4-200), 2- and 5-year local control rates were 91% and 87%, respectively. Preservation of the anal sphincter was achieved in 32 patients (84%). Three patients experienced incontinence after brachytherapy. Only 2 patients showed chronic mucositis grade 3/4. Age proved to be a statistically significant prognostic factor for overall survival in the univariate (p = 0.033) and multivariate analyses (p = 0.018). Concurrent chemotherapy with external beam radiotherapy was a statistically significant prognostic factor for disease-free survival in the univariate and multivariate analyses (p = 0.007 and p = 0.044, respectively). CONCLUSIONS: Interstitial brachytherapy appears to be an effective and well tolerated treatment for anal carcinoma offering both high local tumour control and anal sphincter preservation.

[Surgical treatment of pancreatic adenocarcinoma using cephalic duodenopancreatectomy (Part 2). Long term follow up after 204 cases]. / Tratamiento quirúrgico del adenocarcinoma pancreático mediante duodenopancreatectomía cefálica (parte 2). Seguimiento a largo plazo tras 204 casos.

INTRODUCTION: Surgery is the accepted treatment in adenocarcinoma of the head of the pancreas; however, the long-term survival continues to be low. The aim of this study is to define prognostic factors of long-term survival after cephalic duodenopancreatectomy due to pancreatic adenocarcinoma. MATERIAL AND METHODS: We have collected data on the treatment of adenocarcinoma of the head of the pancreas (ADHP) by means of a cephalic duodenopancreatectomy (CDP) performed n the Bellvitge University Hospital (Barcelona) from 1991 to 2007. RESULTS: A total of 204 CDP due to ADHP were performed. The histology showed that the resected tumour was larger than 3cms in 70 cases, with lymphatic infiltration in 73%, perineural invasion in 89%, and lymphatic involvement in 89%. More than 15 lymph nodes were resected in 120 patients. A total of 113 (60%) patients received adjuvant treatment after surgery. There were 148 (73%) deaths, of which 55 (27%) were alive at closure. The actual mean survival was 2.54 years (95% CI; 2.02-3.07) and an actuarial survival at 5 years of 13.55% (95% CI; 7.69-19.41). The study of mortality risk factors showed that, female gender, absence of peri-operative transfusion (p=0.003), the resection of more than 15 lymph nodes during the operation (P=0.004), and the administration of adjuvant treatment (p=0.004) had a better long-term prognosis. The multivariate analysis showed that transfusion and gender were the most significant variables. CONCLUSIONS: Surgery of head of the pancreas adenocarcinoma must include an adequate lymphadectomy, and must be performed with a low morbidity and without the need of a peri-operative transfusion.

Polymorphisms within inflammatory genes and colorectal cancer.

BACKGROUND: Chronic inflammation is a risk factor for colorectal cancer and polymorphisms in the inflammatory genes could modulate the levels of inflammation. We have investigated ten single nucleotide polymorphisms (SNPs) in the following inflammation-related genes: TLR4 (Asp299Gly), CD14 (-260 T>C), MCP1 (-2518 A>G), IL12A (+7506 A>T, +8707 A>G, +9177 T>A, +9508 G>A), NOS2A (+524T>C), TNF (-857C>T), and PTGS1 (V444I) in 377 colorectal (CRC) cancer cases and 326 controls from Barcelona (Spain). RESULTS: There was no statistically significant association between the SNPs investigated and colorectal cancer risk. CONCLUSION: The lack of association may show that the inflammatory genes selected for this study are not involved in the carcinogenic process of colorectum. Alternatively, the negative results may derive from no particular biological effect of the analysed polymorphisms in relation to CRC. Otherwise, the eventual biological effect is so little to go undetected, unless analysing a much larger sample size.

Polymorphisms of the dopamine receptor gene DRD2 and colorectal cancer risk.

Sporadic colorectal cancer is considered a multifactorial disease in which multiple exposures interact with the individual genetic background resulting in risk modulation. Recent experimental data suggest a role of dopamine and dopamine receptors in the control of proliferation of the cells of colon and gastrointestinal tract. To investigate whether polymorphisms within dopamine receptors genes could have a role in modulating the risk of sporadic colorectal cancer, we did a case-control association study and genotyped 370 cases and 327 controls for seven single-nucleotide polymorphisms (SNP) of DRD2 (-141Cdel, 957T>C, TaqIB, TaqIA, 1412A>G, S311C, and 3208G>T) by a microarray-based technique. Three SNPs within DRD2 were associated with colorectal cancer, with a maximum odds ratio of 2.28 (95% confidence interval, 1.38-3.76) for carriers of the functional SNP -141Cdel. The haplotype which includes -141Cdel, together with the variants 957C and 1412G, shows an odds ratio of 2.86 (95% confidence interval, 1.58-5.18), as compared with the most frequent haplotype. The SNPs within DRD2 associated with colorectal cancer are known to be related to reduced levels of D2 dopamine receptor. Thus, our data point to a possible role of dopamine receptor DRD2 in modulating the risk of colorectal cancer. Future studies on dopamine receptor-mediated signal transduction may provide new insight into the mechanisms of colorectal cancer and suggest new therapeutic strategies.

Sex differences in hospital readmission among colorectal cancer patients.

BACKGROUND: While several studies have analysed sex and socioeconomic differences in cancer incidence and mortality, sex differences in oncological health care have been seldom considered. OBJECTIVE: To investigate sex based inequalities in hospital readmission among patients diagnosed with colorectal cancer. DESIGN: Prospective cohort study. SETTING: Hospital Universitary in L'Hospitalet (Barcelona, Spain). PARTICIPANTS: Four hundred and three patients diagnosed with colorectal between January 1996 and December 1998 were actively followed up until 2002. Main outcome measurements and METHODS: Hospital readmission times related to colorectal cancer after surgical procedure. Cox proportional model with random effect (frailty) was used to estimate hazard rate ratios and 95% confidence intervals of readmission time for covariates analysed. RESULTS: Crude hazard rate ratio of hospital readmission in men was 1.61 (95% CI 1.21 to 2.15). When other significant determinants of readmission were controlled for (including Dukes's stage, mortality, and Charlson's index) a significant risk of readmission was still present for men (hazard rate ratio: 1.52, 95% CI 1.17 to 1.96). CONCLUSIONS: In the case of colorectal cancer, women are less likely than men to be readmitted to the hospital, even after controlling for tumour characteristics, mortality, and comorbidity. New studies should investigate the role of other non-clinical variable such as differences in help seeking behaviours or structural or personal sex bias in the attention given to patients.

[Survival and recurrence in the multidisciplinary approach of colorectal cancer]. / Supervivencia y recidiva en el tratamiento multidisciplinario del carcinoma colorrectal.

BACKGROUND AND OBJECTIVE: Colorectal cancer is one of the most frequent causes of death in the general population. Our aim was to analyze our experience in the multidisciplinary approach of colorectal carcinoma during a three year period. PATIENTS AND METHOD: Between January 1996 and December 1998, we studied prospectively 807 patients with colorectal cancer. The epidemiology, treatment and outcome(recurrence and survival) were analyzed. The minimum follow-up was 3 years. RESULTS: There were 598 colon (65.5%) and 279 rectal (34.5%) tumors in all the series. Surgical treatment was elective in 84% and urgent in 16%, and was considered radical in 598 cases (74.1%). Chemotherapy or radiotherapy was administered in 49.6% and 18.3% patients, respectively. The overall 3-year survival was as follows: stage I 97.5%, stage II 90.6%, stage III 75.2%, and stage IV 12.6%. The 3-year free-disease survival was as follows: in colon cancer 97.8% for stage I, 87.3% for stage II, and 71.4% for stage III; and in rectal cancer 96.8% for stage I, 85.1% for stage II, and 75.4% for stage III. During the follow-up 124 patients (20.7%) developed recurrence: local (2.8%), systemic (15.9%) or both (2%). The three-year survival in operated patients with liver metastases was 61.9%. CONCLUSIONS: We have observed adequate survival and recurrence rates which are the result are of systematic protocols established by a multidisciplinary team.