Survival impact of the Australian National Bowel Cancer Screening Programme.

BACKGROUND: The Australian National Bowel Cancer Screening Program (NBCSP) has been offering age-based faecal occult blood testing since 2006. With the rapid expansion of this programme, the NBCSP will ultimately offer biennial screening to all 50-74 years old by 2020. Participation rates remain low. Previous reports have described an increased proportion of earlier stage cancers in patients with NBCSP-detected tumours. METHODS: Data on consecutive patients enrolled into a prospective, comprehensive, multidisciplinary database at six Victorian hospitals were examined. Clinicopathologic and outcome data were compared for NBCSP and symptomatic presentation patients. RESULTS: We identified 3743 patients that presented with colorectal cancer (CRC) at participating hospitals since May 2006. Of 1930 patients aged between 50 and 70 years, 141 (7.3%) had a NBCSP detected cancer, 1441 (74.7%) presented with symptoms and 266 (13.8%) were diagnosed through screening outside of the NBCSP. Based on the American Society of Anaesthesiology score, the NBCSP patients were fitter. They had an earlier stage of diagnosis and were more likely to be female and less likely to have lymphovascular invasion or to present as an emergency. NBCSP detected patients had a lower rate of recurrence (HR 0.17, P = 0.0001) and fewer deaths (HR 0.19, P = 0.005). CONCLUSIONS: Patients with NBCSP-detected CRC have a markedly reduced risk of CRC recurrence and death compared with patients with a symptomatic presentation. The dominant driver of this appears to be earlier stage at diagnosis. Increased promotion of the impact of the NBCSP, including data related to the survival impact, should be undertaken to increase participation rates and achieve further survival gains.

Predictors of clinic non-attendance: opportunities to improve patient outcomes in colorectal cancer.

AIM: Colorectal cancer is one of the few tumour types, where routine patient follow up has been demonstrated to impact significantly on survival. Patients who fail to attend regular clinic reviews may compromise their outcome, but the frequency at which this occurs is unknown. Identifying the extent of this problem, and the factors that predict non-attendance, may provide opportunities to improve patient outcomes. METHODS: Utilizing the Australian Comprehensive Cancer Outcomes and Research Database (ACCORD) colorectal database at Royal Melbourne and Western Hospitals and the Hospital Patient Management System (HOMER) we collected attendance data for colorectal surgical and oncology outpatient clinic appointments. RESULTS: A total of 619 patients (368 men and 251 women) with curatively treated Australian ClinicoPathological Staging System (ACPS) Stage A, B and C colorectal cancer was identified from the two sites over 1988-2008. Twenty-one per cent (n= 130) of patients failed to attend one or more appointments. Patients who failed to attend were more likely to require the services of an interpreter (25% vs 18%; P= 0.007), to have a smoking history and to have not received adjuvant therapy. Tumour site, patient age, sex and comorbidities were not associated with non-attendance. CONCLUSION: A significant percentage of patients fail to attend routine clinic visits to colorectal speciality clinics. Patients at risk of non-attendance can be identified. More research is needed to identify barriers as to why patients do not attend appointments and to develop measures that may improve patient attendance.

Profuse familial adenomatous polyposis with an adenomatous polyposis coli exon 3 mutation.

The attenuated form of familial adenomatous polyposis coli (AAPC) is associated with mutations in the adenomatous polyposis coli (APC) gene which cluster in the 5' region of the gene. It has been proposed that a 'genotype-phenotype boundary' exists at codons 159-163, and mutations that are 5' of this boundary will produce AAPC. Herein we document a three-generation family with an exon 3 mutation well to the 5' side of the proposed boundary, in which two affected individuals have had, in their 40s, a profuse form of familial adenomatous polyposis coli. We conclude that the codon 159-163 'boundary' is indicative rather than definitive. These two patients also had postoperative intra-abdominal adhesions, severely so in one.

Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/ß-catenin signalling thresholds for tumourigenesis.

Biallelic protein-truncating mutations in the adenomatous polyposis coli (APC) gene are prevalent in sporadic colorectal cancer (CRC). Mutations may not be fully inactivating, instead producing WNT/ß-catenin signalling levels 'just-right' for tumourigenesis. However, the spectrum of optimal APC genotypes accounting for both hits, and the influence of clinicopathological features on genotype selection remain undefined. We analysed 630 sporadic CRCs for APC mutations and loss of heterozygosity (LOH) using sequencing and single-nucleotide polymorphism microarrays, respectively. Truncating APC mutations and/or LOH were detected in 75% of CRCs. Most truncating mutations occurred within a mutation cluster region (MCR; codons 1282-1581) leaving 1-3 intact 20 amino-acid repeats (20AARs) and abolishing all Ser-Ala-Met-Pro (SAMP) repeats. Cancers commonly had one MCR mutation plus either LOH or another mutation 5' to the MCR. LOH was associated with mutations leaving 1 intact 20AAR. MCR mutations leaving 1 vs 2-3 intact 20AARs were associated with 5' mutations disrupting or leaving intact the armadillo-repeat domain, respectively. Cancers with three hits had an over-representation of mutations upstream of codon 184, in the alternatively spliced region of exon 9, and 3' to the MCR. Microsatellite unstable cancers showed hyper-mutation at MCR mono- and di-nucleotide repeats, leaving 2-3 intact 20AARs. Proximal and distal cancers exhibited different preferred APC genotypes, leaving a total of 2 or 3 and 0 to 2 intact 20AARs, respectively. In conclusion, APC genotypes in sporadic CRCs demonstrate 'fine-tuned' interdependence of hits by type and location, consistent with selection for particular residual levels of WNT/ß-catenin signalling, with different 'optimal' thresholds for proximal and distal cancers.

Long-term outcomes of patients with localized rectal cancer treated with chemoradiation or radiotherapy alone because of medical inoperability or patient refusal.

PURPOSE: The standard management of rectal cancer continues to be defined by the results of randomized, clinical trials exploring the optimal timing and use of adjuvant chemotherapy and radiation therapy in relation to surgery. The patient with rectal cancer who is elderly and/or has significant comorbidities and the patient who refuses surgery are clinical contexts for which there is limited current data to guide decision making. METHODS: A retrospective analysis was performed at six Australian centers of patients with rectal cancer treated with radiation therapy or chemoradiation alone because of excessive operative risk or patient refusal of surgery. RESULTS: We identified 48 patients treated between August 1998 and June 2005 with a median age of 76 (range, 49-94) years. Twenty-four patients (50 percent) were considered medically inoperable and 24 patients refused surgery. Treatment was with chemoradiation (with 5-fluorouracil) in 36 patients and radiotherapy alone in 12 patients; 93 percent completed the planned therapy. A clinical complete response was seen in 56 percent and a partial response in 30 percent of patients. At a median follow-up of 49 months, 18 patients have disease progression, including 10 of 24 in the medically inoperable group and 8 of 24 in the refused surgery group. Of the 25 deceased patients, 16 died from progressive disease and 9 from noncancer causes. CONCLUSIONS: Chemoradiation or radiotherapy alone is a safe alternative that results in significant progression-free and overall survival times in patients who are considered medically inoperable or refuse to undergo surgery. Ultimately, however, many patients will progress.

Evaluation of the use of computed tomography versus conventional orthogonal X-ray simulation in the treatment of rectal cancer.

The aim of this study is to compare and contrast the treatment fields designed using CT versus conventional orthogonal X-ray simulation in the treatment of patients with rectal cancer given preoperative chemotherapy and radiotherapy. Nine patients participated in this study. The coverage of treatment fields, the volume of treatment fields, and the position of the anorectal junction in relation to the inferior border of the obturator foramen as the delineator of the pelvic floor were evaluated in each patient using CT and conventional orthogonal X-ray simulation. The results demonstrated undercoverage of the anterior border of the lateral fields of up to 2.5 cm in seven of nine patients when conventional orthogonal X-ray simulation was compared to CT simulation. In addition, the inferior border of the obturator foramen proved to be a poor delineator of the pelvic floor with the anorectal junction situated up to 2 cm superiorly in seven of nine patients. In conclusion, CT simulation is superior to conventional orthogonal X-ray simulation when designing treatment fields for patients with rectal cancer.

Ectopic pregnancy after tubal sterilization.

A case of ectopic pregnancy which occurred 10 months after laparoscopic sterilization by the application of a Hulka clip is reported. Although ectopic pregnancy after other forms of tubal sterilization is well recognized, such pregnancies are rare when tubal-occlusion clips are used. The mechanism of pregnancy in this case is discussed.

PIP: A case of ectopic pregnancy which occurred 10 months after laparoscopic sterilization with a Hulka clip is reported. On laparotomy, a left salpingo-oophorectomy was performed but the right tube with the clip was in place and was left intact. When tubal occlusion has been complete, recovery of tubal potency may occur and proliferation of tubal epithelium has been observed histologically to progress to complete tubal recanalization. Also the production of tissue necrosis leading to the formation of a tuboperitoneal fistula may occur in 2.1-3.6% of cases. If the diameter of the recanalized tube or tuboperitoneal fistula is less than 0.013 cm, interruption to the passage of the ovum will occur and an ectopic pregnancy will result. Other experiences with tubal occlusion devices, including Hulka clips and falope silastic rings, indicate that ectopic pregnancy is extremely rare since the clips only occlude, rather than cut and necrose the tube, so that fistula formation is unlikely. In this patient the right tubal clip was not completely occluding the lumen.

Colonic volvulus. Etiology and management.

Colonic volvulus accounts for 1-7% of cases of large bowel obstruction in the United States and Western Europe. It is, however, a much commoner condition in parts of Africa, South Asia and South America. Volvulus is thought to be an idiopathic condition, probably with an anatomical basis, particularly in cecal volvulus. Some cases are, however, secondary to a known condition such as Chagas' disease. The sigmoid colon is involved in 65-80% of cases and the right colon in 15-30%. Transverse colon and splenic flexure volvulus are rare. Emergency surgery has in the past been associated with a high mortality. Nonoperative, tube decompression of sigmoid volvulus has been the single most important advance in the management of the condition--this has allowed surgery to be deferred to an elective schedule and performed on a fitter patient with a prepared bowel. Emergency surgery is still required for a minority of patients--those in whom tube decompression is unsuccessful; in those with signs of gangrenous bowel and patients with volvulus proximal to the sigmoid. When the bowel is not viable, resection is mandatory. In patients with a viable colon, there are several options. Sigmoid resection and colostomy for sigmoid volvulus and detorsion, cecopexy and tube cecostomy as a combined procedure for cecal volvulus are the usually recommended procedures.

The use of transanal rectal advancement flaps in the management of fistulas involving the anorectum.

Between 1981 and 1986, transanal rectal advancement flaps were employed in the surgical management of 39 anorectal fistulas at the Cleveland Clinic. Included were 23 low rectovaginal, 12 fistulas-in-ano and, four rectourethral fistulas. Nineteen fistulas occurred in patients with Crohn's disease while the other 20 included 11 due to obstetric or surgical injury. This technique has become the Clinic's standard management for low rectovaginal fistulas but is reserved for complex fistulas-in-ano. Active proctitis or malignancy are contraindications to the procedure. Surgery requires elevation of a broad-based rectal flap, curettage of the tract, and advancement and primary suture of the flap over the internal opening. Fistulas were eradicated in 27 cases (69.2 percent) including 11 of 19 due to Crohn's disease (57.9 percent) and 16 of the 20 (80.0 percent) from other causes (mean follow-up, 25 months). Rectovaginal fistulas healed in 60.0 percent of those with Crohn's disease compared with 76.9 percent of those due to other causes. Complex fistulas-in-ano in Crohn's disease did less well. Only two of six of these fistulas healed. Temporary stomal diversion was used on nine occasions and a successful outcome was achieved in only four, indicative of the greater complexity of these cases. It is concluded that the transanal rectal advancement flap can be an effective method of repair for fistulas of the anorectal region including selected cases due to Crohn's disease.

Small colorectal polyps. Are they worth treating?

The histology of small (less than or equal to 0.5 cm.) colorectal polyps removed during total colonoscopy in 303 patients was reviewed to determine their clinical significance. There were 178 male patients and 125 females, with a median age of 64 years (range, 26 to 97 years). A total of 766 polyps were treated, 60 percent being adenomatous and 22 percent hyperplastic. Hyperplastic polyps were more common in the rectum (71 percent) while adenomas were more common in the colon (63 percent). Hyperplastic polyps in the colon were associated with adenomas in 75 percent of cases and hyperplastic rectal polyps were associated with proximal adenomas in 63 percent. There were six mixed hyperplastic/adenomatous polyps. Of the 458 adenomas, 449 were tubular, eight were tubulovillous, and one was villous. Moderate dysplasia was noted in 23 (5 percent) and severe dysplasia in four (0.9 percent). There were associated large adenomas in 84 patients. Small colonic polyps are usually adenomatous and should be destroyed. Biopsy may be important if no other neoplasm has been identified. Small rectal polyps are usually hyperplastic but may be associated with proximal adenomas. Because of the uncertain significance of hyperplastic polyps they should also be treated, and are a relative indication for total colonoscopy.

Rectourethral fistulas in Crohn's disease.

Rectourethral fistula is an uncommon complication of Crohn's disease. When the rectum is apparently spared of active Crohn's disease, repair by an advancement flap of the rectum may be used, with or without temporary fecal diversion. Three such fistulas were reported successfully using this technique.

Definitive management of rectal cancer by contact (endocavitary) irradiation.

In a retrospective review, 62 patients treated for rectal cancer by contact (endocavitary) irradiation at The Cleveland Clinic Foundation were analyzed. This treatment modality delivers high dose, low penetration irradiation to a rectal cancer by direct contact of a 50 KV x-ray source through a special proctoscope. Cancers selected for this treatment include small (3 cm or less), mobile tumors without presacral lymphadenopathy that are within reach of digital examination and are well- or moderately well-differentiated adenocarcinomas. Between 1973 and 1984, 62 patients (37 males, 25 females) were treated--46 by contact irradiation alone and 16 by contact irradiation after excisional biopsy. The median tumor dose was 12,000 rads administered in four fractions at monthly intervals. Mean follow-up was 31 months. Fifty-six patients (90 percent) were disease-free at the time of review or death (ten died from unrelated causes). Eleven patients (18 percent) developed local recurrence but eight of these without distant metastases were rendered disease-free by other treatment--six by surgical resection and two by further radiotherapy. Mean time since secondary treatment is 20 months. Three patients are alive with incurable disease and three have died from cancer--in three of these six patients there was no evidence of local disease. Ulcerated tumors developed local recurrence in five of 17 cases (29 percent) while polypoid tumors recurred locally in six cases (14 percent). Morbidity from the treatment was minor in nature. It is suggested that contact (endocavitary) irradiation is effective treatment for carefully selected cases of rectal cancer.

Desmoid tumors in familial polyposis coli.

Desmoid tumors are locally invasive, nonmetastasizing fibrous tumors most frequently seen in patients with familial polyposis coli (FPC). Of 325 patients with FPC treated at the Cleveland Clinic, 29 (8.9%) were found to have a total of 36 desmoid tumors. These tumors occur in young patients (mean age: 29.8 years), particularly women (ratio 3:1), and most appeared after previous colectomy (86%). The majority (72% of all desmoids, 90% of patients) were located within the abdomen, specifically within the mesentery of the small intestine. In most cases, attempts at surgical resection were followed by recurrence, and other previous treatments were similarly ineffective. Six of the 29 patients (21%) died from the desmoid and three died from other causes. The recent use of sulindac (Clinoril) has produced some early encouraging results in four patients with these tumors that have proven so difficult to treat in the past.