A Review of Controversies in the Management of Colorectal Cancers

Abstract

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Due to a higher incidence of CRC in the western hemisphere a significant amount of research was carried out and majority of the controversies could be resolved as far as management of CRC is concerned. Recently a number of significant advances were made in the field of CRC related to surgery, systemic therapy and radiotherapy. During the last decade we have witnessed introduction of minimally invasive surgery, incorporation of more effective newer chemotherapeutic regimes and targeted therapies and refinements in radiotherapy protocols. The demographics and clinical picture of CRC seems to be different in developing countries and there is paucity of CRC related studies from developing countries. In-order to update the practicing surgeons a review of conventional controversies of CRC surgery was performed and an update on the recent developments in the field of CRC was also presented in this article.

Introduction

Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide [1] Worldwide estimated incidence of colorectal cancer is 20.3/100 000 new cases in 2008[2]. In India, colorectal cancer ranks 8th among all cancers in both sexes with an incidence of 3.8 per 100,000 population. Hospital based and population based data shows that the incidence rates for rectal cancer is higher than colon cancer in all parts of India [3–5]. The profile of CRC patients in the west is different from the profile of Indian CRC patients. In countries with high CRC incidence colon cancer is twice as common as rectal cancer and in countries with low incidence they have an equal distribution [2].

Even though surgery is the mainstay of CRC management, adjuvant chemotherapy and radiotherapy are increasingly being used to improve survival. There are many areas of controversies due to lack of convincing evidence related to diagnostic workup, surgical protocols and adjuvant therapy issues related to chemo and radiotherapy. However during the last three decades a number of multicentre prospective randomized trials (RCTs) were carried out in the field of CRC and the data is helping in the formulation of guidelines for CRC management. In this article a literature search was made for the best available scientific evidence on various surgical and adjuvant therapy issues related to CRC and an attempt was made to summarize the controversial issues related to the management of CRC.

Controversies in the Management of Colorectal Cancers

Surgical Issues in Colorectal Cancer

1. Mechanical bowel preparation:

   Traditionally majority of colorectal surgeons use mechanical bowel preparation prior to colorectal surgery. However there are controversies regarding the need for such a policy. A variety of preoperative protocols are followed for elective colorectal surgery. This includes restricting patient’s diet to fluids for 2 days prior to surgery, administration of mechanical cleansing agent (containing polyethylene glycol or sodium phosphate) and administration of oral antibiotics. In a recent meta-analysis Wille-Jorgensen et al. [6] analysed 5,805 patients (18 RCTs) comprising 3 groups (mechanical bowel preparation group, no preparation group and rectal enemas). Analysis revealed no statistically significant differences between 3 groups in terms of leakage, mortality rates, peritonitis, need for reoperation, wound infection, and other non-abdominal complications. They concluded that there is no evidence that mechanical bowel preparation improves the outcome for patients. Bowel cleansing should be considered when a surgeon needs to identify pathology–for example, a small tumour–or when an intra-operative colonoscopy is planned.

2. Antibiotic prophylaxis:

   Elective colorectal resections are clean contaminated surgeries which require prophylactic antibiotics. There is a lot of heterogeneity in practice guided by hospital policies and individual training and experience. Controversies involve type of antibiotics, route of administration and duration of therapy. In a major cochrane reviewed by Song et al. [7] involving 182 trials including 30,880 colorectal surgery patients the following outcomes were documented as far as the antibiotic usage in colorectal surgery is concerned. There was a statistically significant difference in postoperative surgical site infection (SSI) when prophylactic antibiotics were compared to placebo/no treatment (relative risk (RR) 0.30, 95 % confidence intervals (CI) 0.22 to 0.41). No statistically significant differences were shown when comparing short- and long-term duration of prophylaxis (RR 1.06, 95 % CI 0.89 to 1.27); or single dose versus multiple dose antibiotics (RR 1.17, 95 % CI 0.67 to 2.05). Additional aerobic coverage and additional anaerobic coverage both showed statistically significant improvements in SSI rates (RR 0.41, 95 % CI 0.23 to 0.71 and RR 0.55, 95 % CI 0.35 to 0.85, respectively); as did combined oral and intravenous antibiotic prophylaxis when compared to intravenous alone (RR 0.55, 95 % CI 0.41 to 0.74), or oral alone (RR 0.34, 95 % CI 0.13 to 0.87). They concluded antibiotics covering aerobic and anaerobic bacteria should be delivered orally and intravenously prior to colorectal surgery as it will reduce SSI by 75 %. Further research is required to establish the optimal timing and duration of dosing, and frequency of longer-term adverse effects such as Clostridium difficle associated pseudo membranous colitis.

3. Extent of Resection Margins:

   1. Colonic cancer:
      In general for colon cancer the extent of bowel resection is determined by the location of the tumor and the extent of removal of blood supply and lymphatic supply which should ideally be at the level of the origin of the primary feeding vessel. When primary tumor is equidistant from two feeding vessel, both vessels should be excised at their origin. The length of terminal ileum resection does not affect local recurrence.
      A margin of 5 cm on either side has been proposed by some authors, the rationale being that a minimum margin of 5 cm is needed on either side to remove the draining pericolic and paracolic nodes [8, 9]. The basis of this evidence is from retrospective analysis of resected pathologic specimens and mapping of lymphatic metastases [10, 11].
   2. Rectal cancer:

      • Longitudinal Margins: Longitudinal margin in rectal cancer especially the distal one is crucial because of the issue of sphincter salvage. During the last 3 decades distal margin rectal cancer has shifted from a 5 cm in 70s to 1 cm distal margin in the current era of multi modality therapy. Few recent studies have shown excellent local control can be expected with sphincter-preserving surgery for distal rectal cancers having resection margins of less than 1 cm when TME is combined with preoperative chemo radiotherapy, preoperative short-course radiotherapy, or postoperative chemo radiotherapy [12]. Sondenna et al. [13] compared distal resected margin based on the different methods of measurement by pathologist. The margin was significantly less in unpinned specimen than the pinned specimen which shows the importance of processing the specimen for margin evaluation.
      • Circumferential Resection Margins (CRM): Rectal cancer has a tendency for transmural spread through the rectal wall into perirectal soft tissues contained in the mesorectum. The incidence of pelvic recurrence with conventional blunt surgery techniques for rectal cancer resection varied from 15 to 45 % [14, 15]. To overcome this problem the concept of Total Mesorectal Excision (TME) to achieve adequate CRM was introduced by Heald and colleagues [16]. They emphasized the importance of the proper plane of dissection that encompasses the mesorectum containing the lymphatic channels draining the rectum with autonomic nerve preservation (ANP) to avoid urinary and sexual dysfunction. They reported 3 % local recurrence at 5 years in 519 consecutive rectal cancer patients following TME [17]. A large national cohort study which included 3,319 patients (The Norwegian Rectal Cancer Project) was conducted from 1993 to 1997 to assess the impact of training the surgeons in TME. It showed a 22 % local recurrence rate among patients with a positive CRM (<1 mm margin) compared to a 5 % local recurrence rate among patients with a negative CRM. They found that the TME group did better compared to the conventional surgery group with respect to local recurrence rate (6 % vs. 12 %) and 4 year survival rate (73 % vs.60 %)²⁰. The current reported local relapse with TME is less than 5 % [18, 19]. Apart from a good surgical technique for TME, following a standard histopathology evaluation protocol is equally important as shown by Quirke and Nagtegaal et al. [20]. The pathologist’s macroscopic evaluation of TME specimens is important for three main reasons: first, it provides feedback on surgical technique to the surgeon; second, assessment of the CRM is the most significant predictor of local recurrence; and third, the quality of the excised mesorectum is a key factor affecting the risk of local recurrence in patients with a negative CRM

4. High versus Low Vascular Ligation:

   To achieve an optimal lymphovascular clearance during rectal cancer surgery two surgical approaches are described–low ligation (ligation of Superior Rectal pedicle) or high ligation (ligation of Inferior mesenteric pedicle). In a recent review by Titu L V et al. [21]concluded high ligation of the IMA can be performed safely and does not represent a source of increased morbidity in surgery for rectal and left colonic cancers. High tie leads to improved lymph node harvest, thus facilitating accurate tumour staging. The technique of high ligation of the IMA and IMV is simple. It facilitates complete mobilization of the left colon and helps fashion a tension-free anastomosis, ensures complete excision of the entire lymph-node-bearing mesocolon, and prevents potential intravascular dissemination of cancer cells during tumour manipulation. But a large French multicenter randomized trail [22] comparing low versus high ligation did not show any survival advantage with high ligation.

   At present there is lack of clear cut evidence pertaining to this issue and a routine low ligation with sampling of higher nodes in suspicious cases is also acceptable in general practice. It needs further studies to sort the issue of high tie versus low tie in rectal cancer surgeries.

5. Stapler versus Hand sewn Anastomosis:

   Technological advances made in the field of surgery had a major impact on surgical practice during the last three decades. Staplers were introduced to facilitate the intestinal anastomosis with less contamination, blood loss and decreased operating time. In a early meta-analysis conducted in 2002 comparing 9 RCTs including 1,233 patients comparing stapler versus hand sewn for colorectal anastomosis by Lustosa et al. [23] reported lack of evidence regarding superiority of staplers over hand sewn anastomosis. However recent update of metaanalysis by the same author in 2012 found no new RCTs in the last decade [24]. But in a large Cochrane review by Choy PYG et al. [25] found that stapled anastomosis in ileo-colic anastomosis had fewer leaks compared with hand sewn, being 1.3 % and 6.7 % respectively. Overall, there was no significant difference in the other outcomes. The choice of which technique is applied depends on the surgeon’s personal preferences, clinical circumstances and available resources.

6. Temporary fecal diversion:

   Anastomotic leak following colorectal surgery contributes to major morbidity and mortality. Various factors can affect the incidence of anastomotic leak including the experience of the surgeon, status of the bowel preparation, vascularity, tension at anastomotic site, and technique of anastomosis. Temporary proximal diversion in the form of ileostomy or colostomy is generally used to avoid major morbidity of leak following colorectal surgery. Dehni et al. [26] in a retrospective analysis of 258 consecutive patients with mid-rectal cancers found that in the low rectal resection group without a defunctioning stoma, a clinical leak occurred in 17.0 % whereas leak rate was 6.6 % in the group with a defunctioning stoma. In general a temporary faecal diversion is indicated in old age, low rectal anastomoses, pre operative radio/chemoradiotherapy and sub-optimal anastomoses.

   There is also controversy regarding type of diversion to be performed–ileostomy versus colostomy Gaunega et al. [27] in a review of diversion procedures including five randomised trials showed that, except for stomal prolapsed which was higher in colostomy group none of the outcomes reported were statistically or clinically significant between two procedures. The basic advantages of ileostomy are simplicity of performance, better odour, and ease of appliance change.

7. Drain versus No drain:

   Routinely majority of surgeons use a pelvic drain following rectal cancer surgery to avoid pelvic sepsis. However the review of literature did not support this approach. In a meta analysis of the 1,140 patients enrolled (6 RCTs), 573 were allocated for drainage and 567 for no drainage concluded that there is insufficient evidence showing that routine drainage after colorectal anastomoses prevents anastomotic and other complications [28].

8. Trans Anal Excision of Rectal Cancer:

   This approach is appropriate for early stage (T1N0),small (<3 cm), involving less than 30 % of circumference, well to moderately differentiated tumors located within 8 cm of anal verge. It involves full thickness excision of tumor with margins performed perpendicularly through the bowel wall in to the perirectal fat using a microscope. Advantage of this procedure includes minimal morbidity, mortality, rapid post operative recovery and sphincter salvage. However accurate preoperative staging using a transrectal ultrasound or MRI and surgical expertise is mandatory. A recent retrospective study of 282 patients showed local recurrence of 13.2 % in transanal excision compared to 2.7 % for radical resection(P = 0.001)[29]. In routine clinical practice in India a small subset of patients are suitable for such approach.

9. Restorative Surgical Options–Pouch versus No pouch

   After coloanal reconstruction, many patients experience functional deficiencies, such as increased bowel frequency, urgency and faecal incontinence. This is known as “low anterior resection syndrome” and has been reported in up to 60 % of patients and is due to the loss of rectal reservoir function. The intensity of these symptoms may decrease over the years following surgery.

   A variety of restorative surgical (long J pouch, Side-to end, coloplasty) procedures have been propagated with each one claiming superiority over the others. A small randomized trial [30] comparing J pouch with straight anastomosis showed an initial advantage for J pouch regarding the frequency and soiling rates only during the first 6 months following surgery. Joo et al. [31] in a retrospective study compared 39 patients who underwent coloanal straight anastomosis with 44 patients who underwent colonic J pouch and observed that the J pouch group had lesser number of bowel movement per day, lesser incidence of urgency and incontinence when compared to the straight anastomosis group. They also observed that this advantage was prominent only during the first year after surgery. Harris et al. [32] in a similar study comprising 119 patients reported functional advantage for J pouch patients even at 9 years follow up.

   In recent Cochrane review, Brown C J et al. [33] have shown that after low anterior resection for rectal cancer, coloanal reconstruction with the colonic J pouch leads to better bowel function and similar rates of postoperative complications when compared to the straight coloanal anastomosis. This improved bowel function seems to persist up to 2 years after gastrointestinal continuity is re-established, and thereafter functional outcomes are similar between the two procedures.

10. Role of Minimally Invasive Surgery:

    1. Colonic cancer: The role of laparoscopic surgery in certain benign G.I conditions is well established. Minimally invasive, laparoscopically assisted surgery was first considered in 1990 for patients undergoing colectomy for cancer.
       In multicentre COLOR (Colon cancer Laparoscopic or Open Resection) trial, 627 patients were randomly assigned to laparoscopic surgery and 621 patients to open resection. It was observed that the laparoscopic group had less blood loss, early recovery of bowel function, comparable extent of resection of bowel and lymph nodes and shorter hospital stay.
       In the CLASSICC study 794 patients of colorectal cancer were randomized between laparoscopic versus open surgical approach and at 3 years follow up there was no statistically significant difference in overall survival.
       The COST (The Clinical Outcomes of Surgical Therapy Study group) trial [34] assigned 872 patients with adenocarcinoma of the colon to undergo open or laparoscopically assisted colectomy. Perioperative recovery was faster in the laparoscopic-surgery group than in the open-colectomy group, as reflected by a shorter median hospital stay and briefer use of parenteral narcotics and oral analgesics. At 7 years, the rates of recurrence were similar in both the arms. The overall survival rate at 3 years, the rates of intraoperative complications, 30-day postoperative mortality, complications at discharge and 60 days, hospital readmission, and reoperation were similar between the two groups.
       A cochrane review by Schwenk W et al. [35] in 2005 showed short term advantages of laparoscopy surgery which included less pain, better pulmonary function, shorter time for return of bowel function (duration of postoperative ileus), less fatigue, better quality of life and improved convalescence.
       In 2008 Cochrane [36] review including 12 trials, evaluated oncological outcomes comparing laparoscopic assisted approach with open surgery. The rates of loco-regional recurrence and cancer related mortality were comparable in laparoscopic and open surgery arms, thus establishing the role of laparoscopic surgery in colon cancer.
    2. Rectal cancer: Early reports of laparoscopic surgery for rectal cancer were dominated by sphincter ablating resections. Progress in technology and skills has led to extension of minimally invasive techniques for sphincter preservation also.
       In CLASSICC trial half of the 794 patients were diagnosed with rectal cancer. No significant differences in terms of disease-free survival rate, local recurrence rate, mortality, morbidity, anastomotic leakage, resection margins, or recovered lymph nodes were found. There is evidence that laparoscopic total mesorectal excision (LTME) results in less blood loss, quicker return to normal diet, less pain, less narcotic use and less immune response. It seems likely that LTME is associated with longer operative time and higher costs. Based on evidence mainly from non-randomized studies in recent Cochrane review [37] in 2008, LTME appears to have clinically measurable short-term advantages in patients with primary resectable rectal cancer. The long-term impact on oncological endpoints awaits the findings from large on-going randomized trials.

11. Management of Hepatic Metastases:

    Up to 50 % of patients with colorectal cancer develop metastases, out of which half are isolated to the liver and 10 % to 25 % are eligible for resection. Following surgical resection these patients have a 30 % to 50 % chance of survival at 5 years [38]. Selection criteria for surgery are a residual liver volume of ≥30 % after resection, the feasibility of an R0 resection (clear resection margin), limited or no presence of extrahepatic disease and good performance status of the patient. Although patients with solitary metachronous liver metastases have a better survival compared with patients with synchronous metastases, the presence of synchronous liver metastases should not be a contraindication for surgery, as 5-year survival of up to 31 % can be obtained by resection of synchronous metastases.

    Evidence-based guideline on management of colorectal liver metastases in the Netherlands[39] concluded that even though survival after simultaneous resection of colorectal cancer and liver metastases and resection of liver metastases after an interval of 2 to 3 months are comparable, simultaneous resection should be avoided, due to the high complication rate especially with major hepatic resections. In addition, in two-thirds of patients major hepatic surgery is avoided, because of the detection of an increased number of hepatic or distant metastases after an interval of 2 to 3 months.

    A significant number of colorectal cancer patients present with unresectable hepatic metastases at the time of diagnosis. Previously these patients were offered only palliative chemotherapy. But with the advent of newer and active chemotherapeutic and targeted therapy agents, nowadays Neoadjuvant chemotherapy (NACT) followed by curative hepatic resections are being described in literature. Adam et al. [40] reported Five and 10-year overall survival rates of 33 % and 27 % for a group of patients undergoing NACT followed by hepatic resection.

    In patients not suitable for surgery and not responding to NACT various options including trans-arterial chemoembolization (TACE), Radio frequency ablation (RFA) and cryotherapy can be tried.

Adjuvant Therapy Issues

A detailed discussion on adjuvant therapy controversies in colorectal cancer is beyond the scope of the article. Hence a brief review of crucial adjuvant therapy issues are discussed.

1. Adjuvant therapy in resectable colon cancer:

   Adjuvant chemotherapy plays an important role in colon cancer while radiotherapy has a very limited role. There is no benefit in stage I disease and there is a clear-cut benefit in stage III colon cancer for adjuvant chemotherapy. However in stage II colon cancer role of adjuvant chemotherapy is controversial.

   Some patients with high risk stage II disease have a relapse rate approaching that of stage III colon cancer patients. High risk features include tumours which penetrate the bowel wall, adhere or invade surrounding structures, perforation, obstruction, poorly differentiated tumours, extramural vascular invasion and aneuploidy. Due to the effectiveness of systemic chemotherapy in stage III disease, a similar approach has been considered for patients with stage II disease with high risk features.

   A recent Cochrane analysis[41] concluded that there was no improvement in overall survival in the pooled analysis, but did find that disease-free survival in patients with stage II colon cancer was significantly better with the use of adjuvant therapy. There exists a need to further define which high-risk features in stage II colon cancer patients should be used to select patients for adjuvant therapy. Also, researchers must continue to search for other therapies which might be more effective, shorter in duration and less toxic than those available today.

   Fluorouracil (5FU) based chemotherapy used to be the cornerstone of systemic treatment for colorectal cancer previously. However during the last 2 decades more effective systemic therapy agents have been introduced to clinical practice including Oxaliplatin, Irinotecan, capcetabine, bevacizumab and cetuximab. Current popular chemo regimes for colorectal cancer include FOLFOX and FOLFIRI [42, 43].

2. Adjuvant Therapy in Rectal cancer:

   Unlike colon cancer both chemo and radiotherapy (RT) play an important role in rectal cancer. Radiotherapy has shown to decrease local recurrence and improve survival in locally advanced rectal cancer patients.

   As far as RT is concerned the controversies revolve around timing, dose and sequencing with chemotherapy. As far as timing is concerned the superiority of PreOp RT was proven over Post Op RT in many randomized trials [44, 45]. As far as dose is concerned the controversy is between Short course preoperative RT consisting 25 Gy/5 fractions over 5 days and conventional RT consisting of 45 Gy/25 fractions over 5 weeks. A recent meta analysis by Ceelen W P et al.[46] did not reveal any significant advantage of one over other.