Treatment Of Locally Advanced Rectal Cancer Research Articles

Implications of recent neoadjuvant clinical trials on the future practice of radiotherapy in locally advanced rectal cancer.

Over the last two decades, the standard treatment for locally advanced rectal cancer (LARC) has been neoadjuvant chemoradiotherapy plus total mesorectal excision followed by adjuvant chemotherapy. Total neoadjuvant treatment (TNT) and immunotherapy are two major issues in the treatment of LARC. In the two latest phase III randomized controlled trials (RAPIDO and PRODIGE23), the TNT approach achieved higher rates of pathologic complete response and distant metastasis-free survival than conventional chemoradiotherapy. Phase I/II clinical trials have reported promising response rates to neoadjuvant (chemo)-radiotherapy combined with immunotherapy. Accordingly, the treatment paradigm for LARC is shifting toward methods that increase the oncologic outcomes and organ preservation rate. However, despite the progress of these combined modality treatment strategies for LARC, the radiotherapy details in clinical trials have not changed significantly. To guide future radiotherapy for LARC with clinical and radiobiological evidence, this study reviewed recent neoadjuvant clinical trials evaluating TNT and immunotherapy from a radiation oncologist's perspective.

Rectal Cancer Watch and Wait Approach: A Promising Rectal Salvaging Strategy

1.1. Introduction: Colorectal cancer is the third most common cancer worldwide, with rectal cancer being the 10th fatal cancer. The current recommended treatment for locally-advanced rectal cancer is neoadjuvant chemoradiotherapy followed by surgery, with surgical resection carrying significant postoperative morbidity (intestinal, sexual, urinary) and a negative effect on the quality of life. A newly developed strategy is ‘watch and wait approach’ that renounces surgical resection in the setting of complete clinical response to neoadjuvant chemoradiotherapy only with regular follow ups

Immune Checkpoint Inhibition as a Strategy in the Neoadjuvant Treatment of Locally Advanced Rectal Cancer.

The treatment of locally advanced rectal cancer (LARC) has seen major advances over the past 3 decades, with multimodality treatment now standard of care. Combining surgical resection with radiotherapy and/or chemotherapy can reduce local recurrence from around 20% to approximately 5%. Despite improvements in local control, distant recurrence and subsequent survival rates have not changed. Immune checkpoint inhibitors have improved patient outcomes in several solid tumor types in the neoadjuvant, adjuvant, and advanced disease setting; however, in colorectal cancer, most clinical trials have been performed in the metastatic setting and the benefits confined to microsatellite instability-high tumors. In this article, we review the current preclinical and clinical evidence for using immune checkpoint inhibition in the treatment of LARC and discuss the rationale for specifically exploring the use of this therapy in the neoadjuvant setting. We summarize and discuss relevant clinical trials that are currently in setup and recruiting to test this treatment strategy and reflect on unanswered questions that still need to be addressed within future research efforts.

Review and Updates on Approaches to Neoadjuvant Chemotherapy in Rectal Cancer

The currently established standard of care treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) and adjuvant fluorouracil and oxaliplatin. The body of evidence that supports this treatment has grown over the last 20 years. However, recent advances and ongoing studies seek to further evaluate the role of neoadjuvant chemotherapy with and without radiation and total neoadjuvant therapy (TNT). In this article, we review the current literature as well as investigate the emerging role of TNT for patients with LARC and comment on updates utilizing combination neoadjuvant chemotherapy in early-stage rectal cancer. Evidence for the current standard of neoadjuvant CRT comes from well-established randomized phase III trials as well as emerging evidence on merits of TNT. There is a growing body of literature including retrospective analysis and ongoing clinical trials that look at upfront induction chemotherapy in addition to CRT prior to surgical resection leading to more effective delivery of systemic therapy and increases in response to treatment. Neoadjuvant combination chemotherapy is also being investigated in early-stage low rectal tumors to see if rates of local excision will increase compared to radical excision. Current evidence continues to support neoadjuvant CRT as the standard treatment for LARC. There is an increasing body of evidence to support TNT in LARC as an effective treatment strategy that better ensures delivery of systemic therapy leading to higher rates of complete response (CR) and is encouraging for the development of non-operative protocols. There is ongoing evaluation looking at the benefit of novel sensitizers added to neoadjuvant therapy and ongoing investigation into upfront combination chemotherapy with selective use of radiation in upper rectal cancers.

PCN150 Watch and WAIT Policy Versus Robotic Surgery for Rectal Cancer: A Cost-Utility (RECCOSTE)

Chemoradiotheray (CR) followed by standard Surgical Resection (SR) is the standard treatment for distal locally-advanced rectal cancer (LARC) patients after a clinical compete response (cCR). Some novel approach suggested better functional results using robotic rectal resection (RRR) or avoiding surgical procedure, called Watch and Wait (WW) strategy. The aim of this study is to compare the clinical outcomes and cost-effective outcomes of WW versus RRR in the treatment of LARC. A Markov model-based, cost-utility analysis estimating mean costs and QALYs per patient was performed to compare SR, RRR and WW strategies for patients achieving a cCR to CRT. Rates of local regrowth, recurrence and distant metastasis were derived from series comparing WW to SR and from our previous comparative study of RRR versus SR. Lifetime incremental cost-utility ratio was calculated between strategies, and sensitivity analysis were performed to study model uncertainly. A willingness-to-pay of 30.000 per Quality Adjusted-Life Year (QALY) was used as a threshold to determine the most cost-effective treatment. The base case 15-years cancer-specific survival was 93.5% (95% confidence interval [CI] 91.5-94.9] on a WW program, compared to 95.9% [95%CI 93.6-97.7] after RRR. WW was dominant relative to RRR with cost savings of $48,566.58 (95%CI $47,635.77 - $49,497.39 ) and incremental QALY of 7.47 (95%CI 1.46 – 7.48). WW was also dominant relative to LRR, with cost savings of $48,764.49 (95%CI $47,768.49 - $49,760.48 ) and incremental QALY of 7.44 (95%CI 7,43 – 7.45). WW remained dominant in sensitivity analysis unless the rate of SR fell to 73.0%). This study provides data of cost-effectiveness differences between SR, RRR, WW approaches in LARC after cCR, showing a benefit for WW.

Watch and wait approach in rectal cancer: Current controversies and future directions.

According to the main international clinical guidelines, the recommended treatment for locally-advanced rectal cancer is neoadjuvant chemoradiotherapy followed by surgery. However, doubts have been raised about the appropriate definition of clinical complete response (cCR) after neoadjuvant therapy and the role of surgery in patients who achieve a cCR. Surgical resection is associated with significant morbidity and decreased quality of life (QoL), which is especially relevant given the favourable prognosis in this patient subset. Accordingly, there has been a growing interest in alternative approaches with less morbidity, including the organ-preserving watch and wait strategy, in which surgery is omitted in patients who have achieved a cCR. These patients are managed with a specific follow-up protocol to ensure adequate cancer control, including the early identification of recurrent disease. However, there are several open questions about this strategy, including patient selection, the clinical and radiological criteria to accurately determine cCR, the duration of neoadjuvant treatment, the role of dose intensification (chemotherapy and/or radiotherapy), optimal follow-up protocols, and the future perspectives of this approach. In the present review, we summarize the available evidence on the watch and wait strategy in this clinical scenario, including ongoing clinical trials, QoL in these patients, and the controversies surrounding this treatment approach.

Short-term outcomes of laparoscopic lateral pelvic node dissection for advanced lower rectal cancer.

The laparoscopic magnified visual effects and evolution of the laparoscopic camera system have recently enabled us to observe details in the deep pelvic floor. Indications of laparoscopic surgery for colorectal cancer have been expanded, and laparoscopic (Lap) lateral pelvic node dissection (LLND) has been introduced in some institutions. We investigated the feasibility of Lap LLND in patients with locally advanced rectal cancer (LARC). Lap LLND was performed in 38 patients diagnosed with cT3-4 or cN1-2 cancer during 2014-2018. We retrospectively analyzed their surgical and short-term outcomes. Laparoscopic surgery was performed in all patients. cStages II/III/IV were found in 6/31/1 patients, respectively. Among them, 25 patients underwent neoadjuvant chemotherapy without radiotherapy. Lap unilateral LLND was performed in 6 patients and Lap bilateral LLND was performed 32 patients. The number of harvested lymph nodes (LNs) were 4 in the unilateral group and 15 in the bilateral group. Operation time was 531min, and blood loss was 105ml. Oral intake has started on postoperative day (POD) 3, and pelvic drain was removed on POD 7. Hospital stay was 18.5days. Seven patients developed a neurogenic bladder (all Clavien-Dindo grade (CD) II and all occured in the bilateral LLND group), one patient developed abdominal bleeding (CD IIIb) and one patient developed anastomotic leakage (CD IIIb). Pathological results revealed 2/5/16/14/1 patients with pStages 0/I/II/III/IV, respectively. Four patients had histopathologically verified lateral pelvic lymph node metastases. There were no local recurrences after curative surgery (median follow-up 24.2months). Although the median follow-up period is relatively short and further follow-up is necessary, oncologically, especially in the point of local control rate, Lap LLND appears to have acceptable in the treatment of LARC without radiotherapy in experienced centers. Further investigations focusing on indications and the Lap LLND procedural technique are required.

Outcome and prognostic factors in 593 non-metastatic rectal cancer patients: a mono-institutional survey

This retrospective study was undertaken to provide more modern data of real-life management of non-metastatic rectal cancer, to compare therapeutic strategies, and to identify prognostic factors of overall survival (OS) in a large cohort of patients. Data on efficacy and on acute/late toxicity were retrospectively collected. Patients were diagnosed a non-metastatic rectal cancer between 2004 and 2015, and were treated at least with radiotherapy. OS was correlated with patient, tumor and treatment characteristics with univariate and multivariate analyses. Data of 593 consecutive non-metastatic rectal cancer patients were analyzed. Median follow-up was 41 months. Median OS was 9 years. Radiotherapy was delivered in pre-operative (n = 477, 80.5%), post-operative (n = 75, 12.6%) or exclusive (n = 41, 6.9%) setting. In the whole set of patients, age, nutritional condition, tumor stage, tumor differentiation, and surgery independently influenced OS. For patients experiencing surgery, OS was influenced by age, tumor differentiation and nodal status. Surgical resection is the cornerstone treatment for locally-advanced rectal cancer. Poor tumor differentiation and node involvement were identified as major predictive factor of poor OS. The research in treatment intensification and in identification of radioresistance biomarkers should therefore probably be focused on this particular subset of patients.

Molecular profiling of locally-advanced rectal adenocarcinoma using microRNA expression (Review).

Treatment for locally-advanced rectal cancer (LARC) typically consists of neoadjuvant chemoradiation followed by total mesorectal excision. Recently, there has been growing interest in non-operative management for patients who are medically-inoperable or wish to avoid surgical morbidity and permanent colostomy. Approximately 50% of patients who receive pre-operative neoadjuvant chemoradiation develop some degree of pathologic response. Approximately 10-20% of patients are found to have a complete pathologic response, a finding which has frequently been shown to predict better clinical outcomes, including local-regional control, distant metastasis and survival. Many recent studies have evaluated the role of molecular biomarkers in predicting response to neoadjuvant therapy. MicroRNAs (miRNAs) are an emerging class of biomarkers that have the potential to predict which patients are most likely to benefit from pre-operative therapy and from a selective surgical approach. Here, we review the published literature on microRNAs as prognostic and predictive biomarkers in rectal cancer after pre-operative therapy. In the future, the development of prospectively validated miRNA signatures will allow clinical implementation of miRNAs as prognostic and predictive signatures in LARC.

Effect of neoadjuvant IMRT for locally advanced rectal cancer on toxicity and pathologic response.

693 Background: Neoadjuvant chemoradiation (NeoCRT) is standard of care for the treatment of locally advanced rectal cancer (LARC). Contemporary radiation techniques may reduce dose to normal organs at risk. Our purpose was to compare clinical outcomes and acute toxicities between standard 3D conformal (3D) and intensity modulated radiation therapy (IMRT). Methods: LARC patients (pts) treated at 4 large academic centers in the US between 2007 and 2016 were reviewed. Pts received 5FU-based NeoCRT concurrently with IMRT or 3D. Pathologic response (PR) was used as a surrogate for clinical outcome, and common terminology for adverse events version 4 was used to grade toxicities, summarized on a 1-5 scale. Toxicity rates were compared using chi-square analysis. Multivariable models were fit adjusting for age, gender, pre-tx CT to identify independent predictors of PR and toxicity. Results: 128 pts were analyzed: 60.1% male and 39.8% female, median age 57.7 years (Range 31-85). Clinical characteristics were similar across RT groups. The outcome of partial and complete PR was similar for IMRT and 3D (48.1%, 23.1% vs 32.2%, 23.7%*), respectively. After adjusting for gender, age, and pre-RT chemotherapy type, IMRT was significantly associated with increased odds for complete and partial response (OR: 2.9, 95%CI 1.2-7.2*). Additionally, IMRT was significantly associated with reduced rates of dehydration, dermatitis, rectal pain, rectal bleeding, diverting ostomy, and trend toward significance for decreased rates of fatigue (p = 0.07) and erythema (p = 0.06) (see table). Overall rates of grade 2 and higher toxicities were significantly reduced in IMRT vs. 3D after adjusting for confounders (OR: 0.27, 95% CI 0.08-0.87*). Conclusions: Neoadjuvant 5FU-based IMRT for LARC leads to reduced acute toxicities and improved PR compared to 3D. Given the challenges associated with prospective validation of these data, IMRT should be considered standard treatment for LARC.[Table: see text]

Acute toxicity after a diverting stoma and spacer prior to chemoradiation in locally advanced rectal cancer

Background and purposeChemoradiotherapy (CRT) followed by surgery is the standard of care for locally advanced rectal cancer (LARC). For grade ⩾3 acute diarrhea there is a relationship between dose and irradiated small bowel volume. The aim of this study was to evaluate whether combined placement of a diverting stoma and sigmoid spacer (DSSS) led to reduced irradiated small bowel volume and less grade ⩾3 acute diarrhea in the treatment of LARC. Materials/methodsBetween 2003 and 2010, 54 of 189 LARC patients treated with CRT in two institutions had a DSSS prior to CRT. Data on patient and treatment characteristics and outcomes were collected retrospectively. Delineation of small bowel was performed with planning CT-scans. CTCAE version 4.0 was used for acute toxicity. ResultsPatients with a DSSS had significantly less small bowel volume irradiated up to doses of 20Gy. This difference was not observed for the higher dose levels. CRT induced grade ⩾3 acute diarrhea was not different between the two groups (8.3% vs. 12.8%; p=0.41). ConclusionDSSS is not clearly beneficial to reduce grade ⩾3 acute diarrhea, and it must be considered whether placement of a DSSS is justified for this purpose.

Lower rates of acute gastrointestinal toxicity with pencil beam proton therapy relative to IMRT in neoadjuvant chemoradiation for rectal cancer.

696 Background: Preoperative chemoradiotherapy (CRT) is standard treatment for locally advanced rectal cancer (LARC). GI toxicity leading to ED visits, hospitalization, and need for IV hydration remains a management challenge. Previous studies have established volume of bowel receiving low dose radiation (V15) as the strongest predictor of GI toxicity. We have previously shown pencil beam scanned proton therapy (PBSPT) is dosimetrically superior to IMRT in LARC with respect to low dose to the bowel. This studycompares the toxicity of patients treated with PBSPT and IMRT in neoadjuvant treatment of LARC. Methods: A retrospective review was conducted of patients treated at the University of Pennsylvania with neoadjuvant 5-FU or capecitabine CRT. Patient and tumor characteristics, treatment, and toxicity data were collected. PBSPT (50.4 Gy RBE to standard volumes) was delivered using either two opposed lateral fields or posterior oblique fields with a patient supine or prone. These patients were registered on a prospective registry study. IMRT plans were delivered with 7-9 field IMRT or volumetric arc therapy in the supine or prone position. Statistical analysis was performed using STATA v12.0. Results: Between 3/2009 and 6/2014, 39 patients treated with IMRT and 26 patients treated with PBSPT were studied. Continuous-infusion 5-FU was administered in 31 (79%) IMRT patients and 16 (62%) PBSPT patients (p = 0.162); the remainder received capecitabine. PBSPT patients had significantly lower rates of acute Grade ≥ 2 diarrhea, 12% versus 39% with IMRT (p = 0.022). On multivariable analysis incorporating the type of chemotherapy, use of PBSPT remained a significant predictor of lower rate of Grade ≥ 2 diarrhea (OR = 0.20, 95% CI 0.05 - 0.82, p = 0.025). There was also a borderline significant reduction in Grade ≥ 2 fatigue with the use of PBSPT, occurring in 8% versus 29% of IMRT patients, p = 0.057. Conclusions: These preliminary results indicate PBSPT is associated with significant reduction in acute Grade ≥ 2 diarrhea compared to IMRT. PBSPT may play an important role in the treatment of LARC, a disease with high cure rate where radiation toxicity should be minimized.

Analysis of recurrence pattern and survival in locally advanced rectal cancer treated with neoadjuvant chemoradiation and surgery: 25 years of experience.

744 Background: The standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiation (CRT) followed by total mesorectal excision (TME). Despite the significant reduction (~ 40%) in local recurrence, the overall survival (OS) and disease free survival (DFS) remain stable during last decade. We aimed to study the pattern of recurrence and it’s relationship with clinico-pathological data in 356 patients with LARC treated with CRT and TME in last 25 years. Methods: From a total of 621 patients, 356 with LARC were analyzed. In 55 (15.4%) the tumor was localized in upper third, in 120 (33.7%) in middle third and in 181 (50.8%) in distal third. The median dose of radiotherapy for the 3 groups was between 47.5 - 48.52 Gy. Chemotherapy was based on 5-FU or capecitabine combined with oxaliplatin. Type of surgery, pathological response grade, circumferential resection margin, lymphovascular invasion, colloid response, local recurrence incidence, distal relapse, OS and DFS were analyzed. Results: The median interval between the end of CRT and surgery was 40 days. 52 low anterior resection were carried-out in upper third (94.5%), 112 (93.3%) in middle third and 92 (50.8%) in distal third. Four patients from the middle third (3.3%) underwent abdominoperineal resection and 72 (39.8%) in the distal location. No differences were observed in number of lymphoid nodes, vascular perineural invasion, and pathological response grade. A pathological complete response was assessed in 5 patients (9.1%) in upper third, in 12 (10%) in middle third, as well in 32 (17.7%) in distal third. Median follow-up of 187 months. The 5-10 year DFS for the 3 groups was 75%, 76%, and 69%, and 75%, 71%, and 66% respectively. The local recurrence rate was 3.6%, 4.2%, and 6.1%. The distal recurrence was more frequent in the lung, 10.9%, 16.7%, 23.8%, with tendency to be significant (p<0.007) in distal third. Conclusions: In spite of the good local control with the association of preoperative CRT and TME in treatment of LARC, the development of distant metastases, especially in distal third, gives rise to new therapeutics schemes. Further research is warranted as to the benefits of adjuvant chemotherapy.

Targeted therapy combined with neoadjuvant chemoradiotherapy for locally advanced rectal cancer

Neoadujuvant chemoradiotherapy combined with total mesorectal excision (TME) is the standard treatment modality for locally advanced rectal cancer (LARC).Targeted drugs in LARC neoadjuvant therapy are well tolerated and safety,but compared with conventional neoadjuvant chemoradiotherapy,the pathologic complete response (pCR) rate is not increased.Large sample randomized controlled trials are needed to confirm the effects of targeted drugs in the neoadjuvant treatment of LARC. Key words: Rectal neoplasms; Receptor, epidermal growth factor; Receptors, vascular endothelial growth factor; Neoadjuvant therapy

Helical tomotherapy combined with capecitabine in the preoperative treatment of locally advanced rectal cancer.

The aim of this study was to evaluate the efficacy of helical tomotherapy plus capecitabine as a preoperative chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). Thirty-six LARC patients receiving preoperative CRT were analyzed. Radiotherapy (RT) consisted of 45 Gy to the regional lymph nodes and simultaneous-integrated boost (SIB) 50.4 Gy to the tumor, 5 days/week for 5 weeks. Chemotherapy consisted of capecitabine 850 mg/m2, twice daily, during the RT days. Patients underwent surgery 6–8 weeks after completion of CRT. Information was collected for patient characteristics, treatment response, and acute and late toxicities. Grade 3/4 (G3+) toxicities occurred in 11.1% of patients (4/36). Sphincter preservation rate was 85.2% (23/27). Five patients (14.3%) achieved pathological complete response. Tumor, nodal, and ypT0-2N0 downstaging were noted in 60% (21/35), 69.6% (16/23), and 57.1% (20/35). Tumor regression grade 2~4 was achieved in 28 patients (80%). After a median follow-up time of 35 months, the most common G3+ late morbidity was ileus and fistula (5.7%, 2/35). The study showed that capecitabine plus helical tomotherapy with an SIB is feasible in treatment of LARC. The treatment modality can achieve a very encouraging sphincter preservation rate and a favorable ypT0-2N0 downstaging rate without excessive toxicity.

Effect of oxaliplatin-containing neoadjuvant chemotherapy on tumor volume in locally advanced rectal cancer and sensitivity of surviving tumor cells to radiotherapy.

3547 Background: The use of oxaliplatin (OXA) is well established in adjuvant and palliative treatment of colorectal cancer (CRC), but its role in neoadjuvant treatment of locally advanced rectal cancer (LARC) is controversial. Data from the ACCORD 12/0405, STAR-01 and NSABBP R-04 trials suggest no additional clinical benefit of adding OXA to fluoropyrimidine-based preoperative chemoradiotherapy (CRT) in LARC. However, the possibility of reducing risk of systemic recurrence and the use of OXA-containing neoadjuvant chemotherapy (NACT) in liver metastasis warrant further clarification of the role of OXA in neoadjuvant treatment of LARC. Methods: We report results from a non-randomized phase II trial of neoadjuvant treatment of 72 LARC patients, receiving two courses of the Nordic FLOX regimen prior to CRT (25 x 2 Gy; weekly OXA; daily capecitabine). Tumor volumes were calculated from MRI scans taken before and after NACT and 4 weeks after CRT completion. Using OXA resistant human CRC cell lines, the impact of previous OXA exposure on radiosensitivity (1-5 Gy) was examined. Results: Median baseline tumor volume was 16.6 cm3 (1.1-293 cm3). All tumors, except one, responded to NACT, leaving a median tumor volume of 5.3 cm3 (0.2-157 cm3), representing a median volume reduction of 63%. In all but three patients, additional tumor volume reduction was observed following subsequent CRT (median tumor volume 5.3 cm3; 0.02-119 cm3; median volume reduction of 68%). Exposure of cell lines to increasing concentrations of OXA resulted in resistance towards the drug. OXA resistant models exhibited increased radiosensitivity compared to OXA sensitive counterparts. Conclusions: OXA-containing NACT led to substantial tumor volume reduction. Additional tumor volume reduction was observed in almost all cases, suggesting that pretreatment with OXA-containing NACT did not preclude tumor response to CRT. Results from experimental models rather suggest that pretreatment with OXA might enhance radiosensitivity of surviving OXA resistant cells. Taken together, our results are in favor of continued exploration of OXA-containing NACT in LARC. Clinical trial information: NCT00278694.

Adaptive radiotherapy for long course neo-adjuvant treatment of rectal cancer

PurposeTo quantify the potential margin reduction with adaptive radiotherapy (ART) during neo-adjuvant treatment of locally-advanced rectal cancer. Methods and materialsRepeat CT scans were acquired for 28 patients treated with 25×2Gy, daily during the first week, and followed by weekly scans. The CTV was delineated on all scans, and shape variation was estimated. Five ART strategies were tested, consisting of an average CTV over the planning CT and one to five repeat CTs. Required PTV margins were calculated for adapted and non-adapted treatment. The strategy with the least PTV volume over the whole treatment was selected and bowel area dose reduction was estimated. ResultsSubstantial systematic and random shape variation demanded for a PTV margin up to 2.4cm at the upper-anterior part of the CTV. Plan adaptation after fraction 4 resulted in a maximum 0.7cm margin reduction and a significant PTV reduction from 1185 to 1023cc (p<0.0001). The bowel area volume receiving 15, 45, and 50Gy was reduced from 436 to 402cc, 111 to 81cc, and 49 to 29cc, respectively (p<0.0001). ConclusionsWith adaptive radiotherapy, maximum required PTV margins can be reduced from 2.4 to 1.7cm, resulting in significantly less dose to the bowel area.

Recommendations and expert opinion on the treatment of locally advanced rectal cancer in Spain

In Spain 22,000 new cases of colorectal cancer are diagnosed each year, with 13,075 deaths resulting from this disease. Around 70% of colorectal cancers are localised in the colon and 30% in the rectum. A group of Spanish experts established recommendations on what would be the best strategy in the treatment of locally advanced rectal cancer (LARC). Adequate assessment of local tumour extension, including high-resolution magnetic resonance imaging and endorectal ultrasound, is essential for successful treatment. The three cornerstones in the treatment of LARC are surgery, radiotherapy and chemotherapy. Most patients will need a total mesorectal excision (TME). Preoperative chemo-radiotherapy (CRT) is preferred for the majority of patients with T3/T4 disease and/or regional node involvement, and adjuvant chemotherapy is recommended after a patient-sharing decision. Capecitabine, after showing a trend in improved downstaging in neoadjuvant stratum and the convenience of its oral administration, represents an alternative to 5-FU as perioperative treatment of LARC.

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

516 Background: Bevacizumab into chemoradiotherapy appears safe and active in locally advanced rectal cancer (LARC).This study evaluates whether the addition of bevacizumab to capecitabine-based chemoradiotherapy in the preoperative treatment of LARC improves pathological complete response rate (pCR). Methods: Open-label, unicentric, phase II study in patients with resectable LARC (stage II or III), with or without nodal involvement and no evidence of distant metastases. Treatment schedule of 4-cycles: bevacizumab administered iv on day 1 (10 mg/kg in the first cycle and 5 mg/kg in the following 3 cycles) and capecitabine (900mg/m2/bid) in the 2nd cycle (5 d/wk) concomitantly with radiotherapy 45Gy (25 fractions of 1.8Gy/day) over 5 weeks. Surgical resection was scheduled 6-8 weeks after therapy completion. Preliminary results from ITT analysis are presented. Results: Of the 43 patients included, 41 comprised ITT population. Baseline characteristics: median age 63 (55-67) years; male 76%; ECOG 0/1 49%/51%; stage T3/N1 80.5%/58.5%; nodal metastases 85%. 39 patients underwent surgery, 9 abdominoperineal and 30 anterior resection. No evidence of metastasis after surgery in 97%. Total mesorectal excision was performed in 69% of patients and 85% underwent R0 resection. Sphincter-preservation was achieved in 79.5%. Downstaging occurred in 82%. Among 39 patients evaluable for pathological response, 7.7% experienced pCR, 69.2% partial response and 20.5% stable disease. Grade 3/4 toxicities: 9.8% lymphopenia (all related to capecitabine and 4.9% to bevacizumab), 2.4% neutropenia (capecitabine-related), 2.4% radiodermatitis (related to RT and capecitabine) and 2.4% vasospastic angina (bevacizumab and capecitabine-related). 13 patients had postoperative complications not treatment-related. The most common were wound infection (6), intra-abdominal collection (3), wound dehiscence (2) and paralytic ileus (2). Conclusions: Preoperative regimen with bevacizumab, capecitabine and RT is active for LARC with promising results of R0 resection, sphincter- preservation and tumour downstaging as well as manageable toxicity. Further studies are ongoing to confirm these data. No significant financial relationships to disclose.

Outcome of preoperative chemotherapy (POC) in locally advanced rectal cancer (LARC): Meta-analysis of randomized clinical trials (RCT)

4085 Background: Besides its large use in clinical practice, till now no definitive data exist supporting the efficacy of POC when combined with radiotherapy in improving the outcomes of LARC. Outcome of our work was supporting the use of POC in LARC, making a systematic review of literature with meta-analysis of RCT. Methods: A systematic review of literature from 1966 to September 2007 was independently performed by two authors (ET and DT). All the RCT comparing POC with total mesorectal excision ± neoadjuvant radiotherapy ± adjuvant radiochemotherapy were considered eligible and included into the analysis. Primary end point of our work was the 5-years overall survival (OS); Locale Relapse Risk Reduction (5LRRR), and pathologic complete remission rate (pCR) the secondary ones. A further sub-analysis of Sphincter-Sparing Surgery rate (SSS) was performed including uniquely the trials reporting the datum. Heterogeneity between the trials was assessed using the Mantel-Haenszel test, and the pooled Odds Ratios (ORs) were calculated using a random effects model and an alpha error<5%. Results: Eleven trials (4,515 patients) were considered eligible and included into the analysis. Heterogeneity between the trials was documented respectively in 5LRRR (p=0.027), pCR (p=0.038) and SSS (p=0.014), with a trend for OS (p=0.08). No differences between the groups were observed for 5OS (OR=1.151 p=0.169), while a significant improve in 5LRRR (OR=1.503 p=0.015) and pCR (OR=3.127 p<0.001) was observed in patients treated with POC. A trend in favour of POC (without reaching statistical significance) was observed in SSS (OR=1.253, p=0.079). Conclusions: Besides the heterogeneity between the trials, our data seem to confirm the role of POC in the treatment of LARC: its role seems to be mainly related with the local control of the disease, while no definitive data exist about overall survival. Further trials are probably needed to better define the role of POC in improving the outcomes of LARC; likewise a better definition of the meaning of pCR as a surrogate prognostic and predictive factor after surgery is probably needed to better understand the role of POC in the treatment of LARC. No significant financial relationships to disclose.