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1.  A phase II trial of neoadjuvant IMRT-based chemoradiotherapy followed by one cycle of capecitabine for stage II/III rectal adenocarcinoma 
Neoadjuvant chemoradiation has become the standard treatment in locally advanced rectal cancer (LARC) and improves local control. This study explored the feasibility of an intensified chemoradiation treatment followed by one cycle of capecitabine before surgery for LARC.
Methods and materials
Patients with histologically confirmed, newly diagnosed, locally advanced rectal adenocarcinoma (cT3-T4 and/or cN+) located within 12 cm of the anal verge were included in this study. Patients received intensity-modulated radiation therapy (IMRT) to the pelvis (total dose 44 Gy in 20 fractions), as well as concurrent oxaliplatin (50 mg/m2 d1 weekly) and capecitabine (625 mg/m2 b.i.d. d1–5 weekly). One cycle of capecitabine (1000 mg/m2 b.i.d. d1–14) was given two weeks after the completion of concomitant chemoradiation, and radical surgery was scheduled six weeks after chemoradiation.
Between October 2007 and November 2008, a total of 42 patients were enrolled in the study (median age 51 years; 31 male). Of these, 38 underwent surgical resection and 4 refused radical surgery because of almost complete primary tumor regression and complete symptom relief after neoadjuvant therapy. Fifteen patients underwent sphincter-sparing lower anterior resection. Six patients had a pathological complete response (pCR). The incidence of grade 3 hematologic, gastro-intestinal, and skin toxicities were 4.7%, 14.3%, and 26.2%, respectively. Grade 4 toxicity was not observed. Surgical complications (incisional infection within 2–3 weeks after surgery) were observed in 5 patients. Good responders (defined as TRG 3–4) had a significant difference in DFS (81.6% vs. 16.8%, respectively; p = 0.000) and OS (83.9% vs. 40.7%, respectively; p = 0.007) compared to those who were evaluated as TRG 1–2.
Our study indicates that neoadjuvant chemoradiation followed by one cycle of capecitabine before surgery has a good treatment efficacy, with only mild toxicities associated with chemoradiation and acceptable surgical complications. Treatment response was an early surrogate marker and correlated to oncologic prognosis.
PMCID: PMC3680166  PMID: 23718210
Rectal cancer; Intensity-modulated radiation therapy; Neoadjuvant chemoradiotherapy
2.  Prospective Phase II Study of Preoperative Chemoradiation with Capecitabine in Locally Advanced Rectal Cancer 
Capecitabine is an attractive oral chemotherapeutic agent that has a radiosensitizing effect and tumor-selectivity. This study was performed to evaluate the efficacy and toxicity of preoperative chemoradiation therapy, when used with oral capecitabine, for locally advanced rectal cancer.
Materials and Methods
A prospective phase II trial of preoperative chemoradiation for locally advanced adenocarcinomas of the lower two-thirds of the rectum was conducted. A radiation dose of 50 Gy over five weeks and a daily dose of 1650 mg/m2 capecitabine in two potions was administered during the entire course of radiation therapy. Surgery was performed with standardized total mesorectal excision four to six weeks after completion of the chemoradiation.
Between January 2002 and September 2003, 61 patients were enrolled onto this prospective phase II trial. The pretreatment clinical stages were T3 in 64% (n=39), T4 in 36% (n=22) and N1-2 in 82% (n=50) of these patients. Fifty-six (92%) patients completed the chemoradiation as initially planned and a complete resection performed in 58 (95%). Down-staging was observed in 45 patients (74%) and a pathologic complete response in 6 (10%). Among the 37 patients with tumors located within 5 cm from the anal verge on colonoscopy, 27 (73%) underwent a sphincter-preserving procedure. No grade 3 and 4 proctitis or hematological toxicities were observed.
Preoperative chemoradiation therapy with capecitabine achieved encouraging rates of tumor downstaging and sphincter preservation, with a low toxicity profile. This combined modality can be regarded as a safe and effective treatment for locally advanced rectal cancer.
PMCID: PMC2843876  PMID: 20368828
Rectal cancer; Preoperative; Chemoradiotherapy; Capecitabine
3.  Low rectal cancer: Sphincter preserving techniques-selection of patients, techniques and outcomes 
Low rectal cancer is traditionally treated by abdominoperineal resection. In recent years, several new techniques for the treatment of very low rectal cancer patients aiming to preserve the gastrointestinal continuity and to improve both the oncological as well as the functional outcomes, have been emerged. Literature suggest that when the intersphincteric resection is applied in T1-3 tumors located within 30-35 mm from the anal verge, is technically feasible, safe, with equal oncological outcomes compared to conventional surgery and acceptable quality of life. The Anterior Perineal PlanE for Ultra-low Anterior Resection technique, is not disrupting the sphincters, but carries a high complication rate, while the reports on the oncological and functional outcomes are limited. Transanal Endoscopic MicroSurgery (TEM) and TransAnal Minimally Invasive Surgery (TAMIS) should represent the treatment of choice for T1 rectal tumors, with specific criteria according to the NCCN guidelines and favorable pathologic features. Alternatively to the standard conventional surgery, neoadjuvant chemo-radiotherapy followed by TEM or TAMIS seems promising for tumors of a local stage T1sm2-3 or T2. Transanal Total Mesorectal Excision should be performed only when a board approved protocol is available by colorectal surgeons with extensive experience in minimally invasive and transanal endoscopic surgery.
PMCID: PMC4501926  PMID: 26191350
Low rectal cancer; Sphincter preserving surgery; Intersphincteric resection; Anterior Perineal PlanE for Ultra-low Anterior Resection of the Rectum; Total mesorectal excision; TransAnal Minimally Invasive Surgery; Transanal Total Mesorectal Excision; Quality of life; Oncological outcome; Functional outcome
4.  Is Transanal Endoscopic Microsurgery Adequate in the Removal of Rectal Lesions? 
Transanal endoscopic microsurgery (TEM) was developed by G. Buess in 1983 as a minimally invasive surgery for the removal of anorectal lesions that cannot be excised by conventional transanal instruments. TEM uses specialized equipment including an operating proctoscope and insufflator to form an airtight system. We reviewed the experience of a single surgeon using this technique at our institution.
A retrospective and prospective review of all patients who underwent TEM between November 2002 and April 2007 by a single surgeon at our institution was performed. One hundred thirteen patients were identified. All 113 patients had a preoperative enema. Those with rectal lesions also underwent rectal endoscopic ultrasonography (REUS). A single dose of preoperative cefazolin and metronidazole was given before the start of all procedures. All patients were followed with flexible sigmoidoscopy at 1, 6, and 12 months.
A total of 113 patients underwent TEM excision between November 2002 and April 2007. Diagnoses included benign adenomas (64.6%), carcinoid tumors (14.6%), T1 cancers (18.8%), and a small number of T2 cancers (2.1%). The mean distance from the anal verge was 16 cm. Mean operative time was 79 minutes (range, 48–170 minutes). The average blood loss was 100 cc. The average length of hospital stay was less than 24 hours; 92 patients went home the same day. The longest length of stay was 7 days for a patient who had a long segment of carpet adenomas between 14–6 cm and the peritoneum was entered and subsequently closed. However, postoperatively, there was a question of peritoneal signs and the patient was explored. No spillage was found but the presence of clots was found. In one case, the procedure could not be completed due to a tortuous rectum and the patient underwent a low anterior resection instead. Two patients experienced postoperative bleeding that stopped without intervention and did not require transfusion. One patient developed a hematoma that drained on its own. In all cases, postoperative pain was controlled with oral narcotics. Eight patients had a recurrence of their lesion.
Endoscopic removal of adenomatous colorectal polyps during diagnostic procedures is the first-line treatment of such lesions. It is efficient, safe, relatively inexpensive, and associated with the lowest complication rate. However, this is not always possible due to size and/or location limitations. Additionally, adenomas in the middle or upper rectum are difficult to remove using standard transanal excision instruments. In our series, only 5 of 113 patients (4%) experienced any type of complication. These consisted of bleeding and hematoma. This finding is consistent with other evidence in the literature. TEM is an effective treatment for lesions between 6–18 cm. We believe that it is less invasive than abdominal surgery or the Kraske procedure. The need for conversion and the complication rates are low. It is a useful tool for surgeons to excise lesions that cannot be reached by traditional transanal instruments. Of the 8 patients who had recurrences, 6 were benign while 2 were malignant. The 2 patients with malignant recurrences were not candidates for abdominal surgery due to their comorbidities. TEM is adequate for the removal of rectal lesions, providing the patients are appropriate candidates for the procedure.
PMCID: PMC2645510
5.  Surgical treatment for locally advanced lower third rectal cancer after neoadjuvent chemoradiation with capecitabine: prospective phase II trial 
Treatment of rectal cancer requires a multidisciplinary approach with standardized surgical, pathological and radiotherapeutic procedures. Sphincter preserving surgery for cancer of the lower rectum needs a long-course of neoadjuvant treatments to reduce tumor volume, to induce down-staging that increases circumferential resection margin, and to facilitate surgery.
To evaluate the rate of anal sphincter preservation in low lying, resectable, locally advanced rectal cancer and the resectability rate in unresectable cases after neoadjuvent chemoradiation by oral Capecitabine.
Patients and methods
This trial included 43 patients with low lying (4–7 cm from anal verge) locally advanced rectal cancer, of which 33 were resectable. All patients received preoperative concurrent chemoradiation (45 Gy/25 fractions over 5 weeks with oral capecitabine 825 mg/m2 twice daily on radiotherapy days), followed after 4–6 weeks by total mesorectal excision technique.
Preoperative chemoradiation resulted in a complete pathologic response in 4 patients (9.3%; 95% CI 3–23.1) and an overall downstaging in 32 patients (74.4%; 95% CI 58.5–85). Sphincter sparing surgical procedures were done in 20 out of 43 patients (46.5%; 95% CI 31.5–62.2). The majority (75%) were of clinical T3 disease. Toxicity was moderate and required no treatment interruption. Grade II anemia occurred in 4 patients (9.3%, 95% CI 3–23.1), leucopenia in 2 patients (4.7%, 95% CI 0.8–17) and radiation dermatitis in 4 patients (9.3%, 95% CI 3–23.1) respectively.
In patients with low lying, locally advanced rectal cancer, preoperative chemoradiation using oral capecitabine 825 mg/m2, twice a day on radiotherapy days, was tolerable and effective in downstaging and resulted in 46.5% anal sphincter preservation rate.
PMCID: PMC2699338  PMID: 19508705
6.  Transanal endoscopic microsurgery: what indications in 2013? 
Gastroenterology Report  2013;1(2):75-84.
Thanks to major advances in the field of surgical techniques and neoadjuvant chemoradiation therapy, along with more accurate pre-operative staging tools and the widespread introduction of population-based screening programs, treatment of rectal cancer has been evolving over the past few decades, moving towards a more tailored approach. This has brought a shift in the treatment algorithm of benign rectal lesions and selected early rectal cancers, for which today transanal endoscopic microsurgery (TEM) is accepted as an effective alternative to abdominal surgery.
In 2013, topics of controversy are the role of TEM in the treatment of more advanced rectal cancers, in cases of complete pathological response after chemoradiation therapy and the role of TEM as a platform for single-port surgery and NOTES. This article reviews the current indications for TEM and the future perspectives of this approach in the treatment of rectal tumors.
PMCID: PMC3938006  PMID: 24759812
transanal endoscopic microsurgery; full-thickness excision; rectal adenoma; early rectal cancer; chemoradiation; NOTES
7.  Transanal endoscopic microsurgery combined with endoscopic posterior mesorectum resection in the treatment of patients with T1 rectal cancer – 3-year results 
Rectum-sparing transanal endoscopic microsurgery (TEM) is a well-established treatment for T1 rectal cancer (RC). However, it is associated with an increased rate of local recurrence in comparison with extended resection. In most cases this failure is linked to inappropriate case selection and the presence of clinically non-detectable metastases in the regional lymph nodes. Endoscopic posterior mesorectal resection (EPMR) makes it possible to remove the relevant lymphatic drainage of the lower third of the rectum in a minimally invasive way, which in turn can help in adequate tumor staging.
To evaluate the long-term clinical results and influence of combined TEM and EPMR treatment on the anorectal functions.
Material and methods
Ten consecutive patients with T1 RC were operated on using TEM and EPMR as a two-stage procedure between 2007 and 2009.
After a median follow-up of 42.6 (range: 36–80) months, none of our patients complained of symptoms of incontinence apart from one female patient with gas incontinence diagnosed preoperatively. There was no statistically significant difference in basal anal pressure, squeeze anal pressure, high pressure zone length or fecal continence assessed using the Fecal Incontinence Severity Index before and in follow-up months after the procedure. Postoperative morbidity consisted of one hematoma formation and one male patient complaining about sexual dysfunction until 6 months postoperatively. There was no evidence of locoregional recurrence.
Endoscopic posterior mesorectal resection in combination with TEM appears to be safe, feasible and with no impact on the basic anorectal functions in the 3-year follow-up.
PMCID: PMC3983548  PMID: 24729808
transanal endoscopic microsurgery; rectal cancer; endoscopic posterior mesorectal resection
8.  Transanal endoscopic microsurgery: a review 
Canadian Journal of Surgery  2014;57(2):127-138.
Rectal adenomas and cancers occur frequently. Small adenomas can be removed colonoscopically, whereas larger polyps are removed via conventional transanal excision. Owing to technical difficulties, adenomas of the mid- and upper rectum require radical resection. Transanal endoscopic microsurgery (TEM) was first designed as an alternative treatment for these lesions. However, since its development TEM has been also used for a variety of rectal lesions, including carcinoids, rectal prolapse and diverticula, early stage carcinomas and palliative resection of rectal cancers. The objective of this review is to describe the current status of TEM in the treatment of rectal lesions. Since the 1980s, TEM has advanced substantially. With low recurrence rates, it is the method of choice for resection of endoscopically unresectable adenomas. Some studies have shown benefits to its use in treating early T1 rectal cancers compared with radical surgery in select patients. However, for more advanced rectal cancers TEM should be considered palliative or experimental. This technique has also been shown to be safe for the treatment of other uncommon rectal tumours, such as carcinoids. Transanal endoscopic microsurgery may allow for new strategies in the treatment of rectal pathology where technical limitations of transanal techniques have limited endoluminal surgical innovations.
PMCID: PMC3968206  PMID: 24666451
9.  Transanal endoscopic microsurgery for early rectal cancer: single center experience 
The use of transanal endoscopic microsurgery (TEM) is increasing due to the ability to perform minimally invasive local treatment with large full-thickness local excision under improved vision.
To evaluate the initial experience with TEM for early rectal cancer in a single center.
Material and methods
From February 2010 to November 2013 a total of 20 patients underwent TEM for early rectal cancer. Nine were women and 11 men, age range 39 to 88 years (median: 71 years). The postoperative surveillance protocol, which includes rigid proctoscopy, carcinoembryonic antigen (CEA) and endorectal ultrasound every 3 months during the first 2 years, was applied to all patients after TEM.
Final histology revealed 14 (70%) lesions to be T1 and 6 (30%) T2 cancers. There were no postoperative complications. All 6 patients in the pT2 group and those in the pT1 group with unfavorable histology were offered adjuvant chemoradiotherapy or immediate radical surgery. Patients were followed up from 2 to 35 months (median: 21 months). There was one local recurrence (5%) in a patient who refused to undergo abdominoperineal excision for T1 low rectal cancer, had unfavorable histology after TEM, and for which reason underwent postoperative chemoradiation. The patient had abdominoperineal resection 7 months after TEM (rpT2N0M0). One patient was lost to follow-up. The rest of the patients are alive and disease-free.
In our hands, TEM was an alternative to total mesorectal excision in patients with low-risk early rectal cancer. Further follow-up is necessary to evaluate recurrence and survival rates after TEM for patients with invasive rectal cancer.
PMCID: PMC4280406  PMID: 25561999
transanal endoscopic microsurgery; early rectal cancer; recurrence; survival
10.  Rectal cancer: An evidence-based update for primary care providers 
Rectal adenocarcinoma is an important cause of cancer-related deaths worldwide, and key anatomic differences between the rectum and the colon have significant implications for management of rectal cancer. Many advances have been made in the diagnosis and management of rectal cancer. These include clinical staging with imaging studies such as endorectal ultrasound and pelvic magnetic resonance imaging, operative approaches such as transanal endoscopic microsurgery and laparoscopic and robotic assisted proctectomy, as well as refined neoadjuvant and adjuvant therapies. For stage II and III rectal cancers, combined chemoradiotherapy offers the lowest rates of local and distant relapse, and is delivered neoadjuvantly to improve tolerability and optimize surgical outcomes, particularly when sphincter-sparing surgery is an endpoint. The goal in rectal cancer treatment is to optimize disease-free and overall survival while minimizing the risk of local recurrence and toxicity from both radiation and systemic therapy. Optimal patient outcomes depend on multidisciplinary involvement for tailored therapy. The successful management of rectal cancer requires a multidisciplinary approach, with the involvement of enterostomal nurses, gastroenterologists, medical and radiation oncologists, radiologists, pathologists and surgeons. The identification of patients who are candidates for combined modality treatment is particularly useful to optimize outcomes. This article provides an overview of the diagnosis, staging and multimodal therapy of patients with rectal cancer for primary care providers.
PMCID: PMC4491955  PMID: 26167068
Rectal cancer; Diagnosis; Treatment; Review; Primary care
11.  Local excision of rectal schwannoma using transanal endoscopic microsurgery: A case report 
•Extremely rare rectal schwannoma was successfully treated by TEM.•Only 11 cases of anorectal schwannoma have been reported.•TEM is a feasible approach for local excision of rectal tumors.
Schwannoma is a neoplasm originating from the neural crest cells (schwann cells) that form nerve sheaths. These tumors are thought to be benign with little risk of malignant transformation. They rarely affect the gastrointestinal tract, and primary rectal involvement is extremely rare. Until 2013, only 11 cases of anorectal schwannoma have been reported. Optimal surgical treatment of rectal schwannoma has not been established.
We herein describe a 70-year-old woman with a submucosal tumor arising from the posterior wall of the rectum with features mimicking a gastrointestinal stromal tumor. After discussing the operative procedures and obtaining written informed consent, we attempted local excision of the tumor using a transanal endoscopic microsurgery (TEM). The tumor was proved to be S-100 positive schwannoma on immuhistochemical studies. Her postoperative course was uneventful, and there is no evidence of tumor recurrence as of 6 months after surgical excision.
An extremely rare rectal schwannoma was successfully treated using a TEM without compromising anorectal function.
TEM is a feasible approach for local excision of rectal tumors with low risk of malignancy.
PMCID: PMC4275951  PMID: 25437674
Transanal endoscopic microsurgery (TEM); Rectal shwannoma
12.  Sphincter-preserving R0 total mesorectal excision with resection of internal genitalia combined with pre- or postoperative chemoradiation for T4 rectal cancer in females 
AIM: To evaluate the impact of chemoradiation admi-nistered pre- or postoperatively on prognosis in females following R0 extended resection with sphincter-preserving total mesorectal excision (TME) for locally advanced rectal cancer and to assess the association between chemoradiation and intra- and postoperative variables.
METHODS: Twenty-one females were treated for locally advanced but preoperatively assessed as primarily resectable rectal cancer involving reproductive organs. Anterior resection with TME and excision of internal genitalia was combined with neo- or adjuvant chemoradiation. Two-year disease-free survival analysis was performed with the Kaplan-Meier method and log-rank test. The association between chemoradiation and other variables was evaluated with the Fisher’s exact test and Mann-Whitney test.
RESULTS: Survival rate decreased in anaemic females (51.5% vs 57.4%), in patients older than 60 years (41.8% vs 66.7%) with poorly differentiated cancers (50.0% vs 55.6%) and tumors located ≤ 7 cm from the anal verge (42.9% vs 68.1%) but with the lack of importance. Patients with negative lymph nodes and women chemoradiated preoperatively had significantly favourable prognosis (85.7% vs 35.7%; P = 0.03 and 80.0% vs 27.3%; P = 0.01, respectively). Preoperative chemoradiation compared to adjuvant radiochemotherapy was not significantly associated with the duration of surgery, incidence of intraoperative bowel perforation and blood loss ≥ 1 L, rate of postoperative bladder and anorectal dysfunction, and minimal distal resection margin. It significantly influenced minimal radial margin (mean 4.2 mm vs 1.1 mm; P < 0.01).
CONCLUSION: Despite involving internal genitalia, long-term disease-free survival and sphincter preservation may be achieved with combined-modality therapy for females with T4 locally advanced rectal carcinoma. Neoadjuvant chemoradiation does not compromise functional results and may significantly improve oncological outcomes probably due to enhanced radial clearance.
PMCID: PMC4147144  PMID: 17511034
Locally advanced rectal cancer; Anterior resection; Total mesorectal excision; Hysterectomy; Chemoradiation
13.  Tumor deposits in rectal adenocarcinoma after neoadjuvant chemoradiation are associated with poor prognosis 
Although tumor deposits have been associated with poor prognosis in colorectal carcinoma, the prevalence and clinical significance of tumor deposits in rectal adenocarcinoma following neoadjuvant chemoradiation are relatively unexplored. The aims of this study are to assess the clinical significance of tumor deposits in rectal adenocarcinoma patients, including those receiving neoadjuvant therapy. Pathology slides and medical records from 205 consecutive patients who underwent resection for rectal adenocarcinoma between 1990 and 2010 at a single tertiary care center were reviewed. Patients with tumor deposits had higher tumor grade (P=0.006) and worse tumor stage (P<0.001) at presentation than patients without tumor deposits. Among 110 patients who underwent neoadjuvant chemoradiation, tumor deposits were associated with higher rates of lymph node involvement (P=0.035) and distant metastases (P=0.006), and decreased survival (P=0.027). These patients had a trend toward lower treatment response scores (P=0.285) and higher local recurrence (P=0.092). Of 52 patients with tumor deposits, those who underwent neoadjuvant chemoradiation had significantly worse pretreatment stage by endoscopic ultrasound (P=0.001) but interestingly had significantly lower rates of lymphovascular invasion on resection (P<0.001) compared with those who had not received neoadjuvant chemoradiation. Despite treatment with neoadjuvant chemoradiation, tumor deposits were present in over one-fifth of rectal adenocarcinoma patients. Overall, the outcome of patients with tumor deposits in treated and untreated patients were similar, however the association of tumor deposits with deeply invasive tumors and less tumor regression when comparing with treated patients without tumor deposits raises the possibility that these tumors could have a more aggressive biology, possibly explaining the association of tumor deposits with higher rates of recurrence and lower survival after neoadjuvant chemoradiation. Overall, tumor deposits appear to be a poor prognostic marker among rectal adenocarcinoma patients following neoadjuvant chemoradiation and may identify a subset of patients who require aggressive adjuvant therapy to prevent recurrence.
PMCID: PMC4230335  PMID: 24434897
neoadjuvant treatment; rectal carcinoma; tumor deposits
14.  Current experience and future directions of completely NOTES colorectal resection 
Clinical implementation and widespread application of natural orifice translumenal surgery (NOTES) has been limited by the lack of specialized endoscopic equipment, which has prevented the ability to perform complex procedures including colorectal resections. Relative to other types of translumenal access, transanal NOTES using transanal endoscopic microsurgery (TEM) provides a stable platform for endolumenal and direct translumenal access to the peritoneal cavity, and specifically to the colon and rectum. Completely NOTES transanal rectosigmoid resection using TEM, with or without transgastric endoscopic assistance, was demonstrated to be feasible and safe in a swine survival model. The same technique was successfully replicated in human cadavers using commercially available TEM, with endoscopic and laparoscopic instrumentation. This approach also permitted complete rectal mobilization with total mesorectal excision to be performed completely transanally. As in the swine model, transgastric and/or transanal endoscopic assistance extended the length of proximal colon mobilized and overcame some of the difficulties with TEM dissection including limited endoscopic visualization and maladapted instrumentation. This extensive laboratory experience with NOTES transanal rectosigmoid resection served as the basis for the first human NOTES transanal rectal cancer excision using TEM and laparoscopic assistance. Based on this early clinical experience, NOTES transanal approach using TEM holds significant promise as a safe and substantially less morbid alternative to conventional colorectal resection in the management of benign and malignant colorectal diseases. Careful patient selection and substantial improvement in NOTES instrumentation are critical to optimize this approach prior to widespread clinical application, and may ultimately permit completely NOTES transanal colorectal resection.
PMCID: PMC2999239  PMID: 21160873
Colorectal diseases; Transanal endoscopic microsurgery; Natural orifice translumenal endoscopic surgery
15.  A phase II study of capecitabine and irinotecan in combination with concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of locally advanced rectal cancer 
British Journal of Cancer  2007;96(6):912-917.
We sought to evaluate the efficacy and safety data of a combination regimen using weekly irinotecan in combination with capecitabine and concurrent radiotherapy (CapIri-RT) as neoadjuvant treatment in rectal cancer in a phase-II trial. Patients with rectal cancer clinical stages T3/4 Nx or N+ were recruited to receive irinotecan (50 mg m−2 weekly) and capecitabine (500 mg m−2 bid days 1–38) with a concurrent RT dose of 50.4 Gy. Surgery was scheduled 4–6 weeks after the completion of chemoradiation. A total of 36 patients (median age 62 years; m/f: 27:9) including three patients with local recurrence were enclosed onto the trial. The median distance of the tumour from the anal verge was 5 cm. The main toxicity observed was (NCI-CTC grades 1/2/3/4 (n)): Anaemia 23/9/−/−; leucocytopenia 12/7/7/2, diarrhoea 13/15/4/−, nausea/vomiting 9/10/2/−, and increased activity of transaminases 3/3/1/−. One patient had a reversible episode of ventricular fibrillation during chemoradiation, most probably caused by capecitabine. The relative dose intensity was (median/mean (%)): irinotecan 95/91, capecitabine 100/92). Thirty-four patients underwent surgery (anterior resection n=25; abdomino-perineal resection n=6; Hartmann's procedure n=3). R0-resection was accomplished in all patients. Two patients died in the postoperative course from septic complications. Pathological complete remission was observed in five out of 34 resected patients (15%), and nine patients showed microfoci of residual tumour (26%). After a median follow-up of 28 months one patient had developed a local recurrence, and five patients distant metastases. Three-year overall survival for all patients with surgery (excluding three patients treated for local relapse or with primary metastatic disease) was 80%. In summary, preoperative chemoradiation with CapIri-RT exhibits promising efficacy whereas showing managable toxicity. The local recurrence and distant failure rates observed after a median 28 months are low compared with standard 5-fluorouracil based therapy.
PMCID: PMC2360100  PMID: 17325705
capecitabine; irinotecan; locally advanced rectal cancer; chemoradiotherapy
16.  Transanal endoscopic surgery in rectal cancer 
World Journal of Gastroenterology : WJG  2014;20(33):11538-11545.
Total mesorectal excision (TME) is the standard treatment for rectal cancer, but complications are frequent and rates of morbidity, mortality and genitourinary alterations are high. Transanal endoscopic microsurgery (TEM) allows preservation of the anal sphincters and, via its vision system through a rectoscope, allows access to rectal tumors located as far as 20 cm from the anal verge. The capacity of local surgery to cure rectal cancer depends on the risk of lymph node invasion. This means that correct preoperative staging of the rectal tumor is necessary. Currently, local surgery is indicated for rectal adenomas and adenocarcinomas invading the submucosa, but not beyond (T1). Here we describe the standard technique for TEM, the different types of equipment used, and the technical limitations of this approach. TEM to remove rectal adenoma should be performed in the same way as if the lesion were an adenocarcinoma, due to the high percentage of infiltrating adenocarcinomas in these lesions. In spite of the generally good results with T1, some authors have published surprisingly high recurrence rates; this is due to the existence of two types of lesions, tumors with good and poor prognosis, divided according to histological and surgical factors. The standard treatment for rectal adenocarcinoma T2N0M0 is TME without adjuvant therapy. In this type of adenocarcinoma, local surgery obtains the best results when complete pathological response has been achieved with previous chemoradiotherapy. The results with chemoradiotherapy and TEM are encouraging, but the scientific evidence remains limited at present.
PMCID: PMC4155346  PMID: 25206260
Rectal cancer; Rectal adenocarcinoma; Transanal endoscopic microsurgery; Transanal endoscopic surgery; Colorectal cancer
17.  Short–term effects of neoadjuvant chemoradiation therapy on anorectal function in rectal cancer patients: a pilot study 
Neoadjuvant chemoradiation therapy followed by curative surgery has gained acceptance as the therapy of choice in locally advanced rectal cancer. However, deterioration of anorectal function after long-course neoadjuvant chemoradiation therapy combined with surgery for rectal cancer is poorly defined. The aim of this study was to evaluate the physiological and clinical change of anorectal function after neoadjuvant chemoradiation therapy for rectal cancer.
We analyzed 30 patients on whom preoperative anorectal manometry data were available both before and after chemoradiation from October 2010 to September 2011. All patients underwent long-course neoadjuvant chemoradiation therapy. We compared manometric parameters between before and after neoadjuvant chemoradiation therapy.
Of 30 patients, 20 were males and 10 females. The mean age was 64.9 ± 9.9 years (range, 48-82). Before nCRT, the rectal compliance was higher in patients with ulceroinfiltrative type (P = 0.035) and greater involvement of luminal circumference (P = 0.017). However, there was the tendency of increased rectal sensory threshold for desire to defecate when the patient had decreased circumferential ratio of the tumor (P = 0.099), down-graded T stage (P = 0.016), or reduced tumor volume (P = 0.063) after neoadjuvant chemoradiation.
Neoadjuvant chemoradiation therapy did not significantly impair overall sphincter function before radical operation. The relationship between tumor response of chemoradiation and sensory threshold for desire to defecate may suggest that neoadjuvant chemoradiation may be helpful for defecatory function as well as local disease control, at least in the short-term period after the radiation in locally advanced rectal cancer patients.
PMCID: PMC3766044  PMID: 23961877
Anorectal function; Neoadjuvant chemoradiation; Manometry; Rectal cancer
18.  Concomitant boost IMRT-based neoadjuvant chemoradiotherapy for clinical stage II/III rectal adenocarcinoma: results of a phase II study 
This study was designed to evaluate the efficacy and toxicities of concomitant boost intensity-modulated radiation therapy (IMRT) along with capecitabine and oxaliplatin, followed by a cycle of Xelox, in neoadjuvant course for locally advanced rectal cancer.
Materials and methods
Patients with histologically confirmed, newly diagnosed, locally advanced rectal adenocarcinoma (cT3-T4 and/or cN+) located within 12 cm of the anal verge were included in this study. Patients received IMRT to the pelvis of 50 Gy and a concomitant boost of 5 Gy to the primary tumor in 25 fractions, and concurrent with oxaliplatin (50 mg/m2 d1 weekly) and capecitabine (625 mg/m2 bid d1–5 weekly). One cycle of Xelox (oxaliplatin 130 mg/m2 on d1 and capecitabine 1000 mg/m2 twice daily d1–14) was given two weeks after the completion of chemoradiation, and radical surgery was scheduled eight weeks after chemoradiation. Tumor response was evaluated by tumor regression grade (TRG) system and acute toxicities were evaluated by NCI-CTC 3.0 criteria. Survival curves were estimated using the Kaplan-Meier method and compared with Log-rank test.
A total of 78 patients were included between March 2009 and May 2011 (median age 54 years; 62 male). Seventy-six patients underwent surgical resection. Twenty-eight patients underwent sphincter-sparing lower anterior resection and 18 patients (23.7%) were evaluated as pathological complete response (pCR). The incidences of grade 3 hematologic toxicity, diarrhea, and radiation dermatitis were 3.8%, 10.3%, and 17.9%, respectively. The three-year LR (local recurrence), DFS (disease-free survival) and OS (overall survival) rates were 14.6%, 63.8% and 77.4%, respectively. Initial clinical T stage and tumor regression were independent prognostic factors to DFS.
An intensified regimen of concomitant boost radiotherapy plus concurrent capecitabine and oxaliplatin, followed by one cycle of Xelox, can be safely administered in patients with locally advanced rectal cancer, and produces a high rate of pCR. A prognostic score model is helpful to distinguish different long-term prognosis groups in early stage.
PMCID: PMC3984733  PMID: 24606870
Rectal cancer; Intensity-modulated radiation therapy; Concomitant boost; Neoadjuvant chemoradiotherapy
19.  Transanal Endoscopic Microsurgery for the Treatment of Well-Differentiated Rectal Neuroendocrine Tumors 
Recently, an increase in well-differentiated rectal neuroendocrine tumors (WRNETs) has been noted. We aimed to evaluate transanal endoscopic microsurgery (TEM) for the treatment of WRNETs.
Between December 1995 and August 2009, 109 patients with WRNETs underwent TEM. TEM was performed for patients with tumors sizes of up to 20 mm and without a lymphadenopathy. These patients had been referred from other clinics after having been diagnosed with WRNETs by using a colonoscopic biopsy; they had undergone a failed endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR) and exhibited an involved resection margin and remaining tumor after ESD or EMR, regardless of the distance from the anal verge. This study included 38 patients that had more than three years of follow-up.
The mean age of the patients was 51.3 ± 11.9 years, the mean tumor size was 8.0 ± 3.9 mm, and no morbidity occurred. Thirty-five patients were asymptomatic. TEM was performed after a colonoscopic resection in 13 cases because of a positive resection margin, a residual tumor or a non-lifting lesion. Complete resections were performed in 37 patients; one patient with a positive margin was considered surgically complete. In one patient, liver metastasis and a recurrent mesorectal node occurred after five and 10 years, respectively.
TEM might provide an accessible and effective treatment either as an initial or as an adjunct after a colonoscopic resection for a WRNET.
PMCID: PMC3440489  PMID: 22993706
Well-differentiated rectal neuroendocrine tumors; Transanal endoscopic microsurgery; Colonoscopic resection; Treatment
20.  Management of Refractory Metastatic Anal Squamous Cell Carcinoma Following Disease Progression on Traditional Chemoradiation Therapy 
Case Study
Ms. S.G., a 56-year-old woman with a poorly differentiated squamous cell carcinoma of the anal canal, American Joint Committee on Cancer stage III (T2, N1, M0), was initially diagnosed in December, 2007 at an outside institution after she had noted blood in her stool for approximately 6 months. Her medical history was unremarkable. She had no known history of HIV or other sexually transmitted diseases. At the time of presentation, Ms. S.G. had an Eastern Cooperative Oncology Group performance status of 1 related to cancer-related pain. Her appetite and weight were both stable.
A complete colonoscopy demonstrated a large, immobile, ulcerated, firm, 4-cm lesion in the distal rectum, arising from the anal canal. Initial staging positron emission tomography/computed tomography (PET/CT) scan revealed a hypermetabolic inferior anorectal mass with left perirectal and presacral nodal metastases. There was no definite evidence of distant metastatic disease.
Ms. S.G. received chemoradiation treatment following her diagnostic studies, with a total dose of 45 Gy over 26 fractions to the pelvis with concurrent infusional fluorouracil (5-FU; 2, 450 mg over 7 days) and mitomycin C (12 mg/m2 on day 1) at an outside institution. However, during her chemoradiation therapy, Ms. S.G. experienced a 3-week treatment break due to severe radiation dermatitis, as recommended by her outside treating oncologist.
Upon treatment completion, Ms. S.G. underwent a biopsy of the anal canal, which revealed no evidence of residual malignancy. As recommended by her treating oncologist, she received four additional cycles of adjuvant infusional 5-FU in combination with leucovorin. Shortly thereafter, Ms. S.G. developed progressive pelvic pain. She underwent a second PET/CT scan, revealing mixed findings: interval resolution of abnormal standardized uptake value (SUV) activity at the primary tumor in the anal canal, but an increase in the size and SUV of nodal disease within the left perirectal and presacral regions. A CT-guided biopsy noted a perirectal abscess requiring drainage but was inconclusive for disease recurrence; Ms. S.G. was treated with IV antibiotics.
Six weeks later, repeat radiographic imaging noted additional changes suspicious for regional recurrence, which was biopsy-confirmed. Ms. S.G. was subsequently referred to MD Anderson Cancer Center for consideration of salvage pelvic exenteration.
On physical exam a mass was palpated in the left lower quadrant, but there was no evidence of inguinal adenopathy. On digital rectal exam there was notable external erythema with a fixed mass and moderate sphincter tone. A chest CT scan showed no definite evidence of metastatic disease, but an MRI of the abdomen/pelvis indicated the presence of a complex partially necrotic mass (7.6 × 4.9 × 7.3 cm3) extending to the rectosigmoid junction, inseparable from the left lateral bowel wall, with partial encasement of the bowel. In addition, there was infiltration of the left piriformis muscle and cervix consistent with local recurrence. She was referred to medical oncology and radiation oncology for consideration of reirradiation with concurrent neoadjuvant chemotherapy for palliation and possible surgical resection.
In early December 2008, Ms. S.G. received intensity-modulated radiation therapy (IMRT), with a total dose of 27 Gy over 18 fractions. She received concurrent infusional 5-FU at 300 mg/m2/day, from Monday to Friday, on the days of radiation. She also received a weekly bolus dose of cisplatin at 20 mg/m2. The intent was to treat to 30 Gy, but the patient deferred further treatment early due to anorectal irritation. She then underwent restaging with a PET/CT scan and a pelvic MRI in February 2009, revealing radiographic partial response of the known pelvic recurrence and reduced pelvic pain (Figures 1A and 1B). Figure 1 Figure 1. Contrast-enhanced axial MRI image of the lower pelvis. (A) Pretreatment, complex mass at the rectosigmoid junction measuring approximately 7.6 × 4.9 × 7.3 cm3. (B) Posttreatment, large necrotic mass measuring 3–4 cm in greatest dimension.
Unfortunately, in the interim, she developed multiple bilateral liver lesions and punctate pulmonary nodules consistent with distant disease (Figures 2A, 2B, and 3A). Figure 2 Figure 2. Contrast-enhanced axial CT images of the lung. (A) Subcentimeter nodular opacity in the left upper lobe. (B) Subcentimeter opacity in the right upper lung lobe. Figure 3 Figure 3. Contrast-enhanced axial CT image of the liver. (A) Pretreatment, multiple bilateral liver lesions. (B) Posttreatment, near-complete resolution of liver lesions.
Ms. S.G. proceeded to undergo systemic chemotherapy with carboplatin at an area under the concentration-time curve of 5 and paclitaxel at 175 mg/m2 day 1, every 21 days. She tolerated the treatment well. After three cycles of chemotherapy, radiographic imaging indicated a mixed response to treatment: interval resolution of the pulmonary nodules, stability of disease in the pelvic mass, but progression of the hepatic metastases.
Given Ms. S.G.'s continuing excellent performance status, further treatment was recommended. Based on recent published literature, a regimen of cisplatin at 80 mg/m2 day 1, vinorelbine at 25 mg/m2 day 1 (repeated every 28 days), and weekly cetuximab (VCC) at 250 mg/m2 was initiated. Remarkably, following three cycles of treatment, despite receiving multiple prior lines of chemotherapy, her restaging CT scan demonstrated complete radiographic response of the intrathoracic disease, stable response of the anorectal mass, and near-complete resolution of the hepatic lesions (Figures 3A and 3B).
Overall, Ms. S.G. had tolerated her treatment very well. Given her response and tolerability, she was evaluated again for curative surgical resection. However, she opted to receive the VCC regimen closer to home and was lost to follow-up. Unfortunately, we were unable to obtain medical records confirming if she indeed received additional treatment as recommended. Ms. S.G. was noted to have passed away due to progression of her disease approximately 6 months later.
PMCID: PMC4093318  PMID: 25031942
21.  A critical review of the role of local excision in the treatment of early (T1 and T2) rectal tumors 
The optimal treatment of early (T1 and T2) rectal adenocarcinomas remains controversial. Local excision and radical resection with total mesorectal excision are the two surgical techniques for excising early rectal cancer. Each has their respective benefits, with local excision allowing for decreased operative morbidity and mortality while radical resection provides an oncologically complete treatment through lymphadenectomy. Local excision can be accomplished via transanal endoscopic microsurgery or transanal excision. There is no significant difference in the recurrence rates (21% vs. 33%) or overall survival (80% vs. 66%) between the two local excision modalities; however, transanal endoscopic microsurgery does allow for a higher rate of R0 resection. Current selection criteria for local excision include well to moderately differentiated tumors without high-risk features such as lymphovascular invasion, perineural invasion, or mucinous components. In addition, tumors should ideally be <3 cm in size, excised with a clear margin, occupy less than 1/3 of the circumference of the bowel and be mobile/nonfixed. Despite these stringent inclusion criteria, local excision continues to be plagued with a high recurrence rate in both T1 and T2 tumors due to a significant rate of occult locoregional metastases (20% to 33%). For both tumor groups, the recurrence rate in the local excision group is more than double compared to radical resection. However, the overall survival is not significantly different between those with and without metastases. With intense postoperative surveillance, these recurrences can be identified early while they are confined to the pelvis allowing for salvage surgical options. Recently, neoadjuvant therapy followed by local excision has shown favorable short and long-term oncological outcomes to radical resection in the treatment of T2 rectal cancer. Ultimately, the management of early rectal cancer must be individualized to each patient’s expectations of quality and quantity of life. With informed consent, patients may be willing to accept a higher failure rate and an increased post-operative surveillance regimen to preserve a perceived increased quality of life.
PMCID: PMC4173049  PMID: 25276407
Transanal excision; early rectal tumors; local excision
22.  Single incision laparoscopic surgery - trans anal endoscopic microsurgery: A technological innovation 
Trans anal endoscopic microsurgery (TEM) first burst upon the scene several decades ago and then underwent a period of immersion. We have herein reported our experience in two cases who underwent TEM using laparoscopic techniques. The advent of single incision laparoscopic surgery (SILS) has made great inroads into various fields of general and gastrointestinal (GI) surgery. We decided to make use of the same technique in TEM for two patients who had large sessile villous adenomas of the rectum. We used this port and fixed it transanally to the edge of the anus. Carbon dioxide used for insufflation in laparoscopic surgery was used through one of the ports, and a telescope was inserted to the larger port. We made sure that the entire polyp was cut out completely until the circular muscle of the internal sphincter was clearly exposed. Next, the cut edges of the rectum were undermined between the mucosa and the circular muscles in order to bring the cut edges closer together. We were able to perform this SILS TEM in two cases. In both the cases, well differentiated villous adenoma (colonoscopically, biopsy proven before surgery) was confirmed after excision. The question has been raised whether TEM is the new laparoscopy for anorectal surgery. Increasingly, several reports are showing promise for treatment for early stage cancers and large rectal adenomas using TEM. Adoption of our technique using the SILS port that has not been previously described in medical literature, seems to be a promising tool for the future.
TEM first burst upon the scene several decades ago and then under went a period of immersion. In recent years, with the onset of laparoscopic surgery, the thoughts and the ideas of using a laparoscopic surgical technique have invaded the area of colorectal cancer as well. We have herein reported our experience in two cases who underwent TEM using laparoscopic techniques.
PMCID: PMC3996744  PMID: 24761088
Anal canal; single incision laparoscopic surgery; trans anal endoscopic microsurgery; villous adenoma
23.  Treatment of rectal cancer by transanal endoscopic microsurgery: Experience with 425 patients 
AIM: To describe our experience in treating rectal cancer by transanal endoscopic microsurgery (TEM), report morbidity and mortality and oncological outcome.
METHODS: A total of 425 patients with rectal cancer (120 T1, 185 T2, 120 T3 lesions) were staged by digital rectal examination, rectoscopy, transanal endosonography, magnetic resonance imaging and/or computed tomography. Patients with T1-N0 lesions and favourable histological features underwent TEM immediately. Patients with preoperative stage T2-T3-N0 underwent preoperative high-dose radiotherapy; from 1997 those aged less than 70 years and in good general health also underwent preoperative chemotherapy. Patients with T2-T3-N0 lesions were restaged 30 d after radiotherapy and were then operated on 40-50 d after neoadjuvant therapy. The instrumentation designed by Buess was used for all procedures.
RESULTS: There were neither perioperative mortality nor intraoperative complications. Conversion to other surgical procedures was never required. Major complications (urethral lesions, perianal or retroperitoneal phlegmon and rectovaginal fistula) occurred in six (1.4%) patients and minor complications (partial suture line dehiscence, stool incontinence and rectal haemorrhage) in 42 (9.9%). Postoperative pain was minimal. Definitive histological examination of the 425 malignant lesions showed 80 (18.8%) pT0, 153 (36%) pT1, 151 (35.5%) pT2, and 41 (9.6%) pT3 lesions. Eighteen (4.2%) patients (ten pT2 and eight pT3) had a local recurrence and 16 (3.8%) had distant metastasis. Cancer-specific survival rates at the end of follow-up were 100% for pT1 patients (253 mo), 93% for pT2 patients (255 mo) and 89% for pT3 patients (239 mo).
CONCLUSION: TEM is a safe and effective procedure to treat rectal cancer in selected patients without evidence of nodal involvement. T2-T3 lesions require preoperative neoadjuvant therapy.
PMCID: PMC4110589  PMID: 25071352
Rectal cancer; Transanal endoscopic microsurgery; Chemoradiotherapy; Local excision; Downstaging
24.  Neoadjuvant capecitabine, radiotherapy, and bevacizumab (CRAB) in locally advanced rectal cancer: results of an open-label phase II study 
Preoperative capecitabine-based chemoradiation is a standard treatment for locally advanced rectal cancer (LARC). Here, we explored the safety and efficacy of the addition of bevacizumab to capecitabine and concurrent radiotherapy for LARC.
Patients with MRI-confirmed stage II/III rectal cancer received bevacizumab 5 mg/kg i.v. 2 weeks prior to neoadjuvant chemoradiotherapy followed by bevacizumab 5 mg/kg on Days 1, 15 and 29, capecitabine 825 mg/m2 twice daily on Days 1-38, and concurrent radiotherapy 50.4 Gy (1.8 Gy/day, 5 days/week for 5 weeks + three 1.8 Gy/day), starting on Day 1. Total mesorectal excision was scheduled 6-8 weeks after completion of chemoradiotherapy. Tumour regression grades (TRG) were evaluated on surgical specimens according to Dworak. The primary endpoint was pathological complete response (pCR).
61 patients were enrolled (median age 60 years [range 31-80], 64% male). Twelve patients (19.7%) had T3N0 tumours, 1 patient T2N1, 19 patients (31.1%) T3N1, 2 patients (3.3%) T2N2, 22 patients (36.1%) T3N2 and 5 patients (8.2%) T4N2. Median tumour distance from the anal verge was 6 cm (range 0-11). Grade 3 adverse events included dermatitis (n = 6, 9.8%), proteinuria (n = 4, 6.5%) and leucocytopenia (n = 3, 4.9%). Radical resection was achieved in 57 patients (95%), and 42 patients (70%) underwent sphincter-preserving surgery. TRG 4 (pCR) was recorded in 8 patients (13.3%) and TRG 3 in 9 patients (15.0%). T-, N- and overall downstaging rates were 45.2%, 73.8%, and 73.8%, respectively.
This study demonstrates the feasibility of preoperative chemoradiotherapy with bevacizumab and capecitabine. The observed adverse events of neoadjuvant treatment are comparable with those previously reported, but the pCR rate was lower.
PMCID: PMC3179720  PMID: 21880132
capecitabine; chemoradiation; bevacizumab; locally advanced rectal cancer; LARC; phase II study
25.  Transanal endoscopic microsurgery in treatment of rectal adenomas and T1 low-risk carcinomas 
Transanal endoscopic microsurgery as a local therapy option for rectal neoplasms is a tissue-sparing technique that protects the anal sphincter. The present retrospective analysis reports the course of observation after local excision of adenomas and T1 low-risk carcinomas using transanal endoscopic microsurgery.
In a retrospective analysis we examined data on 279 patients for local recurrence. A total of 144 patients had a rectal adenoma (n = 103) or a R0 resection of low-risk T1 carcinomas (n = 41). In this collective, we also examined parameters concerning perioperative management, complications, intraoperative blood loss and duration of hospital stay.
Patients with adenoma were on average 64.9 (range 37 to 90) years old; 83.5% of the adenomas were located 3 to 11 cm from the anocutaneous line. In adenoma patients the recurrence rate was 2.9% for an observation period of 21.8 months. The postoperative course was without any complications in 98.1% of patients.
Patients with T1 low-risk carcinoma were 64.6 (range 30 to 89) years old. In all cases, an R0 resection could be performed. The recurrence rate was 9.8% for an observation period of 34.4 months. In this group the postoperative course was free of complications in 97.6% of patients.
The high efficacy of transanal endoscopic microsurgery ensures minimally invasive treatment of adenomas and low-risk T1 carcinomas with low complication rates and a low rate of therapeutic failure.
PMCID: PMC3556112  PMID: 23181563
Transanal endoscopic microsurgery; Rectal adenoma; Rectal carcinoma; Local excision; Endoscopic surgery

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