Advanced Colorectal Malignancy Research Articles

Colorectal Malignancy Complicated by Arterioenteric Fistula.

Arterioenteric fistulas (AEF) are rare and devastating complications of colorectal/pelvic malignancies. These fistulas can be seen following neoadjuvant or adjuvant therapy but are exceptionally rare de novo. The reported incidence of AEF is less than 1% and iliac artery-enteric fistulas make up less than .1% of all AEF. Here we present a patient in hemorrhagic shock secondary to an advanced colorectal malignancy without adjuvant therapies with local invasion of the right external iliac artery. Following initial resuscitation and hemorrhage control with coil embolization, definitive control with ligation and excision of the involved artery, end colostomy, and ureteral stent placement was achieved. It is important to consider malignancy as the source of lower gastrointestinal bleeds, especially in elderly patients without current colonoscopy studies. The management of this unfortunate diagnosis often involves a multidisciplinary approach with early and frequent goals of care discussions.

Management of Stage 4 Colon and Rectal Cancer

This issue of Clinics in Colon and Rectal Surgery will review the complexities in the management of stage 4 colon and rectal cancer. There has been steady progress in the management of advanced colorectal cancer with improvements in overall survival; however, the treatments must be thoughtful, individualized, and focused on collaboration with the team of oncology specialists to provide the best chance for control of the disease, minimizing morbidity, and optimizing quality of life during and after treatment. The authors have attempted to review the current information related to epidemiology, evaluation, medical, and surgical management, and have attempted to look to the future for additional options for the treatment of our patients with advanced colorectal malignancy.

Prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) for the prevention and control of peritoneal metastasis in patients with gastrointestinal malignancies: a systematic review of randomized controlled trials.

Peritoneal metastasis is associated with poor prognosis, with studies in the literature reporting the survival of peritoneal metastasis without treatment to be three to six months. Hyperthermic intraperitoneal chemotherapy (HIPEC) has shown positive outcomes by improving the prognosis in patients with gastrointestinal malignancies. This systematic review of randomized controlled trials was done to determine the prophylactic role of hyperthermic intraperitoneal chemotherapy in preventing and controlling peritoneal metastasis gastrointestinal origin. Randomized controlled trials published between January 2019 to June 2021 were included. The databases used were MEDLINE (PubMed), EMBASE (Ovid), and the Cochrane library. Cochrane handbook for systematic review of intervention was used to assess the risk of bias in included trials. The results were reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. A total of five trials met the inclusion criteria. Two studies were on patients with gastric cancer, and the other three studies were on patients with colorectal cancer. HIPEC was given to a total of 116 gastric cancer patients and 308 colorectal cancer patients. In all the included studies on patients with gastric cancer, the peritoneal recurrence-free survival was significantly higher in the group that received HIPEC. There was no significant improvement in peritoneal-free survival in patients with colorectal cancer who received HIPEC. HIPEC appears to be effective in preventing peritoneal metastasis in patients with locally advanced gastric cancer without minimal postoperative complications. However, in patients with advanced colorectal malignancy, HIPEC does not seem to play a crucial role in preventing and controlling peritoneal metastasis.

Nature and outcomes of the increased incidence of colorectal malignancy after liver transplantation in Australasia

To examine whether incidence of colorectal malignancy is increased in Australasian liver transplant recipients compared with the general population of Australia, and to assess the characteristics and outcomes of colorectal malignancy in this patient group. Data on patients who underwent orthotopic liver transplantation (OLTx) and had a diagnosis of de-novo colorectal malignancy after transplantation during the period 1985-2011 were obtained from the Australia and New Zealand Liver Transplant Registry, and these data were compared with colorectal malignancy data from the Australian Institute of Health and Welfare. Time from OLTx to diagnosis of colorectal malignancy, stage of colorectal malignancy at diagnosis, patient survival, and standardised incidence ratio (SIR) for colorectal malignancy. Forty-eight of 3735 recipients (1.3%) were diagnosed with colorectal malignancy at a median of 7.3 years after OLTx. More advanced colorectal malignancy (regional or metastatic disease) was evident at diagnosis in 20 of the 48 patients; these patients tended to be younger than patients with less advanced malignancy (P = 0.01) and diagnosed sooner after OLTx (P = 0.005). Despite treatment predominantly with surgery, 19 of the 48 patients died from the malignancy. The overall SIR for colorectal malignancy liver transplant recipients compared with the general population of Australia was 2.80 (95% CI, 2.06-3.71). The incidence of colorectal malignancy is increased in liver transplant recipients in comparison with the general population. Of concern is the tendency for advanced malignancy to be diagnosed in younger patients. These data highlight the importance of considering whether specific guidelines for colorectal malignancy screening in the Australasian adult liver transplant population are needed.

Palliative treatment of malignant colorectal obstruction caused by advanced malignancy: a self-expanding metallic stent or surgery? A system review and meta-analysis

We conducted a meta-analysis to compare the outcomes of a self-expanding metallic stent (SEMS) vs. surgery for the palliative treatment of colorectal obstruction caused by advanced colorectal malignancy. The databases of MEDLINE, EMBASE, Cochrane controlled trials registry and the Chinese Wanfang were retrieved (updated to 31 August 2011) to identify eligible studies. We calculated the odds ratio or weighted mean difference and its corresponding 95% confidence interval. In total, nine primary studies were included in this analysis. The success rate of SEMS placement was 93.9%, with short-term and long-term complication rates of 26.2 and 16.1%, respectively. Combined analyses revealed that the SEMS group had a similar risk of short-term complications as the surgical group (P=0.22). Moreover, SEMS was not associated with a higher mortality risk than surgical intervention (P=0.22) and it required a significantly shorter hospitalization time (P<0.01); however, SEMS patients had a higher risk of long-term complications (P=0.03). Because of great heterogeneities between patients and chemoradiotherapy, we did not analyze the survival times of the two groups. These results support the feasibility of SEMS as a palliative treatment for malignant colorectal obstruction caused by incurable malignancy, as it requires shorter hospitalization and is followed by quick recovery. However, the risk of long-term complications such as perforation and stent migration should be borne in mind.

Nonresectional palliative abdominal surgery for patients with advanced colorectal cancer

Nonresectional palliative abdominal surgery (e.g. defunctioning stoma/bypass) may be appropriate for patients unsuitable for curative resection, to deal with complications of advanced colorectal malignancy such as obstruction. Our aim was to review the outcome of surgery in these patients within our institution. All patients undergoing palliative surgery without resection for colorectal carcinoma between July 1998 and January 2007 were identified from our prospectively compiled colorectal cancer database. Data were extracted related to patients' demographics, presentation, tumour site, operative intervention, complications, oncological therapies, length of hospital stay and postoperative survival. One hundred and ninety-three patients were identified with a median age of 79 years (31-94 years). Fifty per cent were operated on an emergent basis for obstruction or perforation, and 50% on an elective basis. One hundred and sixty-nine patients had defunctioning stomas formed of which 156 were loop stomas. Twenty-four patients underwent bypass procedures. Thirty-day mortality rate was 13.5% and postoperative morbidity rate 47%. Median survival was 247 days, with 1-year survival of 38%. Patients undergoing operation on an emergent basis had poorer long-term survival (127 vs 320 days, P = 0.002). Nonresectional palliative abdominal surgery is associated with relatively high morbidity and mortality, particularly when performed in the emergency setting. However, in this patient group with a very poor outlook, it may be offered with reasonable survival expectations.

Colorectal Cancer

Purpose: Despite directed efforts at increasing awareness and screening for colorectal cancer, patients with regular medical follow-up for other diseases are routinely diagnosed with advanced colorectal malignancy. Methods: We reviewed 37 consecutive patients (23 female, 62%) with advanced colorectal cancer treated by three colorectal surgeons over six months (July 2005 – January 2006). Results: The mean age was 65.5 years. Pre-operative staging was available for 35 patients (II = 6, III = 12, IV = 17). Common presenting complaints were bleeding (n = 23), pain (n = 19), and weight loss (n = 10). Most patients (n = 20) presented to the emergency department with complaints of bleeding (n = 14) or obstruction (n = 4). Mean presenting lab values were: CEA 41.0 ng/ml (range 0.5 – 436), Hematocrit 33.0% (range 22.0 – 50.6), and albumin 3.1 g/dl (range 0.9 – 4.6). Two-thirds had insurance that would have covered cancer screening. 29(78.4%) patients had operations. Five patients were inoperable and three are currently receiving neoadjuvant therapy. Rectal cancers predominated (n = 19) and were more common in males (n = 12). Most patients with rectal cancer required a colostomy (n = 11) or were inoperable (n = 5). Seventeen (58.6%) patients developed post-operative complications; the most common being post-operative ileus (24.1%). Average hospital stay was 10 days. 25 patients received neo-adjuvant chemoradiation therapy, including 5 who received intra-operative radiation for locally advanced disease. Detailed computer medical records were available for 18 patients (48.6%). 14 (77.8%) had an average of 4.64 physician visits in the six months preceding their cancer diagnosis for the treatment of unrelated comorbidities. Four had not been seen because of lack of insurance. Ten (71.4%) had fecal occult blood testing ordered (six not completed with no follow-up, three were negative, one positive with no follow-up). Screening colonoscopy was ordered for two patients; both refused. Conclusions: These results suggest that comorbid diseases may mask symptoms and signs of colorectal cancer and cause appropriate screening to be ignored. Patients with advanced colorectal malignancy present anemic, malnourished, have frequent post-operative complications, long hospital stays, and require more radical operations. Modern use of advanced multidisciplinary treatment and neoadjuvant therapy may offer patients with advanced disease more options today then in the past.

The expression of leptin in colorectal cancer

Introduction: Weight loss is a recognised feature of advanced stage colorectal cancer; the precise aetiology remains obscure. Leptin, a 16 kDa protein and encoded by the ob gene, is sectreted from adipocytes and has been shown to play an important role in the regulation of energy balance and therefore body weight in animal models. Recently, non-adipocyte sources of leptin have been reported. The purpose of our study was to determine whether leptin may playa part in the aetiology of weight loss in colorectal cancer. We therefore assessed leptin expression in colonic mucosa and compared mailgnant to non-malignant tissue specimens. Methods: Twenty-seven cancer and 17 corresponding normal mucosa specimens were collected from patients undergoing surgical resection of colorectal cancer. Samples were mechanically disaggregated and homogenised on ice in lysis buffer. Following centrifugation the supernatant was removed for leptin analysis. Leptin was measured by using a Human Leptin RIA Kit (Linco Research Inc.), which utilises radioaminoassay, and leptin levels were standardised against protein concentration . Results: Leptin was found to be present in both normal and malignant colonic mucosa. The expression of leptin was significantly higher in normal mucosa (mean 1.03 ng/f.Lg protein) when compared to cancer specimens (mean 0.68 ng/f.Lg, p=0.0l5). There was no significant relationship between histophathological stage of cancer and leptin expression. Conclusions: This is the first study demonstrating the presence of leptin in both normal and malignant colonic mucosa. Interestingly, the relatively low leptin levels in colorectal cancers do not appear to explain the weight loss seen in patients with advanced colorectal malignancy. However, whether there is a hypothalamic insensitivity to leptin, as reported in lung cancer patients, remains to be elucidated.

Preclinical and clinical aspects of biomodulation of 5-fluorouracil

Although single agent 5-FU has for many years been the standard therapy for advanced colorectal malignancies, a number of recent clinical trials show higher response rates with biomodulation of 5-FU by several different agents. In general, trials of leucovorin, methotrexate, interferon, and PALA given in biomodulatory doses and sequences with 5-FU have demonstrated comparable response rates over a broad range. However, in the absence of controlled direct comparative phase III trials, final judgement on clinical superiority of a particular regimen must be reserved. Nevertheless, on the basis of current data, certain approaches appear promising and warrant further investigation. Compared to single agent 5-FU, survival benefit has been demonstrated with both low and high dose leucovorin/5-FU regimens and response rates in the 20–50% range appear reproducibly higher than those of 5-FU alone. Low dose and either continuous infusion or repetitive dosing of leucovorin, as well as the effect of treatment sequence and intervals between drugs, require additional investigation. When given 20–24 h before 5-FU, methotrexate achieves response rates similar to leucovorin modulated 5-FU, but the potential role of rescue leucovorin used in many of the trials makes definitive interpretation difficult. Interferon/5-FU regimens attaining response rates of 30–40% are promising but need to be carefully and rationally designed. Low dose PALA with effective doses of 5-FU achieving responses in 35–45% of patients represent a marked improvement in earlier trials of high dose PALA, but additional studies with higher doses not compromising 5-FU dose intensity should be considered. Certainly, the concomitant use of multiple modulating agents also needs further investigation. While many such trials already performed attained results no better than single agent biomodulation, the preliminary results obtained by Grem and colleagues with IFN/LV/5-FU in untreated patients, and by Conti et al. using TMTX/LV/5-FU in previously treated patients are encouraging. Further understanding of the mechanisms of action and interaction of modulating agents should allow additional rational combinations to be explored clinically. Cisplatin biomodulation of 5-FU has been studied in gastrointestinal and head and neck malignancies achieving excellent results in the latter group. Preclinical evidence exists which suggests, however, that 5-FU modulation of cisplatin may be more effective, especially when 5-FU is administered 24 h or more before cisplatin. Clinical investigation of this sequence is currently lacking. Data to support the clinical promise of AZT, IdUrd, uridine, and the benzylacyclouridines are not yet available, although preclinical and preliminary clinical studies are promising.