It has been estimated from global cancer statistics that about 20 % of colorectal cancer patients have distant metastases at the time their primary tumor is discovered.(1)
There are three different Stage 4 situations to be considered in this discussion.
- The most common is the patient with a primary tumor of the large bowel without evidence of obstruction or bleeding that has unresectable metastases in the liver or lung.
- The second situation is the patient with a primary colorectal tumor and unresectable distant metastases who has clinically significant bleeding or obstruction.
- The most favorable but, unfortunately, rarest scenario is the patient with a primary bowel tumor and resectable distant metastases (for cure).
Whereas surgery is indicated for the second and third situations it may not be the best choice for the first scenario. Also it isimportant to recognize that several very different types of bowel operations may be indicated in this patient population. Whereas resection of the primary is necessary if there is an intent to cure or if the lesion is bleeding significantly, simple diversion or intestinal bypass may be the best or only option for patients in the unresectable category. Certainly, when surgery is indicated, minimally invasive approaches should be strongly considered. The more rapid short term recovery is especially advantageous in this population where chemotherapy so often plays a critical role. As alluded to above, the role of bowel resection in the treatment of patients with Stage 4 colorectal cancer with unresectable metastases is decreasing because of the development of improved chemotherapy regimens that can significantly extend the lives of these unfortunate patients. In patients with non-obstructing and non-bleeding lesions there is nothing to be gained, in regards to survival, from removing the primary tumor. In fact, colorectal resection may stimulate the growth of the residual cancer via surgery related proangiogenic blood protein alterations that persist for up to 1 month after surgery.(2) Furthermore, surgery in these patients delays the start of chemotherapy. Thus, it is the opinion of the author that surgery should not be performed primarily in these patients, instead chemotherapy should given first with surgery held in reserve should the patient develop obstruction or bleeding or should the disease be judged resectable for cure as a result of the chemotherapy. In patients with metastases deemed resectable for cure, surgery in general and laparoscopic surgery, in particular, is necessary and appropriate. The most common situation is a patient with one or several liver metastases and a primary colon cancer. Traditionally, the colon tumor would be resected first and the liver tumor several months later provided the liver disease was still resectable and there were no other metastases. In these patients a laparoscopic resection is logical since the recovery period is a bit shorter which should facilitate the performance of the second procedure. Another option for select Stage 4 patients is to do a simultaneous resection of the liver metastasis(es) and the primary. There are even a few surgeons who would resect liver or lung metastases first, leaving the primary tumor in place. It is also logical to use M.I.S. methods in Stage 4 patients who undergo palliative colorectal resection and in whom postoperative chemotherapy is planned because the anti-cancer drugs can usually be started more rapidly owing to the quicker recovery. The final option, not widely practiced presently, is to give preoperative chemotherapy prior to a planned resection.
Port Site Tumors and Early Reluctance to Use MIS Methods for Stage 4 Patients
Initially, during the ‘90’s there was great concern that laparoscopic surgery in the cancer setting, in general, and in the stage 4 setting, in particular, would result in a higher rate of port and wound metastases (vs open surgical methods). For mainly this reason, most surgeons did not ultilize MIS methods for cancer. Further, amongst those surgeons who were performing laparoscopic colectomy for cancer, most initially avoided Stage 4 patients because of the fear of port site or wound recurrences. However, once it was clear that the rate of abdominal wound tumor formation was no higher after laparoscopy than after open surgery, surgeons began performing MIS surgery on these challenging patients. Regardless of whether open or closed surgical methods are utilized, the chances for traumatizing the tumor and spilling viable tumor cells into the abdomen or wound is much greater in the stage 4 setting. The primary tumor is often large and may have penetrated the entire bowel wall; also, there may be multiple metastases throughout the peritoneal cavity. In manipulating the bowel, inserting and maneuvering the instruments, mobilizing and devascularizing the bowel, and removing the tumor/bowel specimen there is risk of shedding tumor cells.
Review of the Literature
The short term outcome of 331 patients with advanced colorectal cancer who underwent palliative laparoscopic surgery and were part of a German multicenter prospective study of laparoscopic colorectal surgery was reviewed by Scheidbach et al in 2007.(3) Of note, 241 patients of the 331 Stage 4 patients underwent resection of the primary tumor whereas 90 (27%) underwent laparoscopic diversion alone. The results of all of the Stage 4 patients (resection and stoma only patients combined) were compared to the results of 3,553 patients with benign pathology who underwent colorectal resection (majority had sigmoid resection for diverticulitis). The best comparison group for the Stage 4 cancer patients would be Stage 1-3 cancer patients who underwent laparoscopic resection as opposed to patients with benign pathology. Also, it must be acknowledged that, ideally, only the Stage 4 cancer patients who had resections would be considered in a comparison to a group of patients who all had M.I.S. resections. Because of these study design problem it is difficult to draw firm conclusions regarding the comparison results. Regardless, this study does provide perioperative data on a large group of Stage 4 M.I.S. patients. Of note, the mean age of the cancer patients (67) was significantly older than that of the benign group (59.2). The overall morbidity (medical + surgical complications) rate for the Stage 4 cancer patients was 29.3% (vs 17.5% for the benign patients) while the postoperative mortality was 6.7 % (vs 0.6% for benign group). The authors suggest that the morbidity difference is due to a significantly higher rate of non-surgical complications in the cancer patients (cardiopulmonary complications, pneumonia, and UTI’s) which they attribute to a difference in the comorbidities between the groups that, in part, may be related to the age difference as well as the presence of a malignancy. The rate of intraoperative complications for the Stage 4 group was 5.1% (vs 4.9%) while the conversion rate was 5.1 % (vs 5.7%). There was no difference in the rate of anastomotic leaks (Stage 4, 4.3%; benign group, 2.4%), wound-related complications (Stage 4 group, 4.2%; benign, 5.5%), or reoperations (stage 4, 3.6%; benign 3.5%). The authors conclude that, in their opinion, laparoscopic techniques are safe and effective, in regards to operative and postoperative complications, for the palliative treatment of advanced colorectal cancers. Fukunaga et al did a retrospectrive analysis that compared the operative and short term outcome results of 65 Stage 4 patients and 513 Stage 1-3 patients that underwent laparoscopic colorectal resection in their institution. (4) The authors acknowledge that not all Stage 4 patients were deemed candidates for M.I.S. methods; those with large rectal tumors that filled the pelvis were excluded. There was no significant difference in the mean age, sex, or the location of the cancers in the Stage 4 M.I.S. patients when compared to the Stage 1-3 M.I.S. patient group. Not surprisingly, there were significantly more T-4 lesions in the Stage 4 group (52%) than in the Stage 1-3 group (13.4%); also, the mean diameter of the cancers was significantly greater in the Stage 4 group. Of note, significantly more of the Stage 4 patients (9 patients, 13.8%) underwent concomitant en bloc resection of an adjacent organ (peritoneum/abdominal wall, 4 pts.; liver, 2 pts.; ovary, 1 pt,; prostate, 1 pt.; duodenum, 1 pt.) than in the Stage 1-3 group (5 pts, 0.97%). It is also important to note that in 21 (32.3%) of the Stage 4 patients the colorectal resection was undertaken with a curative intent. Most of these patients underwent subsequent liver resection or liver tumor ablation at a second operation (13/21). Three Stage 4 patients underwent simultaneous liver and colon resection (4.6%) and 2 patients had undergone previous resection of lung metastases. In the 44 stage 4 patients (66%) who underwent palliative resection, 31 received subsequent chemotherapy while 11 had no other anti-cancer therapy. There was no significant difference between groups in regards to length of surgery (Stage 4, 189 min.; Stage 1-3, 182.5 min), blood loss, overall morbidity (Stage 4, 12.3 %; Stage 1-3, 15.1 %), first flatus (mean 2 days for both groups), or length of stay (Stage 4, 11 days; Stage 1-3, 10 days). Although the conversion rate was higher for the Stage 4 group (4.6%) than in the Stage 1-3 group (2.7%), the difference was not significant. As regards complications, there was no difference in the rate of: anastomotic leakage (Stage 4, 3%; Stage 1-3, 5.1%), anastomotic bleeding (Stage 4, 0%; Stage 1-3, 0.7%), wound infection (Stage 4, 4.6%; Stage 1-3, 5.1%), intrabdominal abscess (Stage 4, 0%; Stage 1-3, 0.2%), or injury of other organs (Stage 4, 0%; Stage 1-3, 0.4%). The authors conclude that laparoscopic colorectal resection is feasible for selected Stage 4 patients and is associated with short term outcomes similar to those noted in the Stage 1-3 patient group. Moloo et al reviewed the results of 49 Stage 4 colorectal cancer patients that underwent palliative laparoscopic resection and compared them to 326 Stage 1-3 M.I.S. resection patients.(5) The Stage 4 patients were significantly older (mean age 78 vs 70) and their tumors significantly larger (mean size 5.4 cm vs 4.6 cm) than the Stage 1-3 group. The breakdown of the operations performed were similar, mostly right and sigmoid resections for both groups. The mean length of operation was also similar. Of note, in only 33% of the Stage 4 patients was it known preoperatively that distant metastases were present; in the remainder it was discovered at surgery. The rate of intraoperative complications was similar for the Stage 4 (4%) and the Stage 1-3 (9%) groups. There was also no significant difference in the incidence of major postoperative complications between the groups (Stage4, 14%; Stage 1-3, 12%); in particular the rate of leaks was 6 % for the Stage 4 patients vs 5% for the Stage 1-3 patients. The perioperative mortality was 8 % for the Stage 4 patients as opposed to 4 % for the Stage 1-3 patients although the difference between groups was not significant (p=0.41). Of note, in this population of patients, the conversion rate was significantly greater for the Stage 4 patients (22%) when compared to the Stage 1-3 group (11%, p=0.05); tumor fixation was the reason for conversion in 7 of the 11 patients (14% of the overall Stage 4 group) who were converted in the Stage 4 group. The authors conclude that laparoscopic-assisted colorectal resection is “safe and technicially feasible” with a morbidity and mortality similar to that observed in Stage 1-3 patients. A smaller review by Gonzalez et al examined the results of 21 palliative laparoscopic operations performed for colorectal cancer related complications including perforation (48%), bleeding (33%), or obstruction (19%).(6) Also of note, all patients had either unresectable distant metastases or carcinomatosis. There is no laparoscopic or open comparison group in this study. A colorectal resection was carried out in 18/21 patients (85%) all of whom were diverted proximally. The remaining 3 patients were diverted only. Half the patients underwent resection with Hartmann’s pouch and proximal colostomy. The conversion rate was 14% (3/21). The mean operative length was 181 minutes and the mean estimated blood loss was 283 ml. The mean length of stay was 8.6 days. There was a single intraoperative complication (enterotomy) and 7 postoperative complications (33%) including lower GI bleeding (3 pts), wound infection (2 pts), ischemic bowel (1 pt), and colostomy retraction 91 pt). There were no perioperative deaths. The authors conclude that laparoscopic methods are safe and effective for this most difficult group of patients.
Laparoscopic Colorectal Resection
The same laparoscopic surgical methods used for Stage 1-3 patients are used for the advanced cases. Only the differences in technique will be discussed here. Certainly
in cases where an attempt will be made to cure the Stage 4 patient, the surgeon must be prepared to resect part of or all of any adjacent organ that is adherent to the cancer (small bowel, bladder, tube, ovary, abdominal wall, parietal peritoneum, etc) in order to fully remove the primary tumor. Even in the instance of a palliative resection, if possible, the primary should be fully removed so as to reduce the local recurrence rate. In contrast, in patients with unresectable distant metastases it is not necessary to do a high ligation of the main feeding vessels of the mesentery since it will not impact the survival. Similarly smaller segmental resections are reasonable in patients with unresectable tumors. In the authors view, in the case of large cancers, hand-assisted laparoscopic methods are logical because an extraction incision close to 8 cm in length is usually required regardless. The hand-assisted resections have been shown to significantly shorter than the laparoscopic assisted equivalent.
Laparoscopic Stoma Creation
Laparoscopic methods are ideal when the goal is simple diversion via a loop ileostomy or colostomy in the setting of obstruction. It is usually possible to accomplish the task with 3 ports, 1 of which is enlarged and through which the bowel is exteriorized. In the case of a colostomy, the location of the primary tumor will guide or determine which colon segment will be targeted for exteriorization. In the case of a loop transverse colostomy for a left sided cancer the overlying omentum must be dealt with either by reflecting it up towards the head and then “peeling” it off the transverse colon or by dividing the gastrocolic ligament so as to permit the colon to be lifted and encircled. In the case of a loop sigmoid or left sided colostomy, because the tumor is often involving the sigmoid or rectosigmoid, it is usually necessary to mobilize at least part of the descending colon in order to obtain the mesenteric length needed to make the stoma. The loop ileostomy is usually the simplest stoma to construct. In this case it is important to locate the cecum in order to verify that the distal ileum is being exteriorized. It is advised that an endoloop type tie be laparoscopically placed on an epiploicae or the bowel itself prior to desufflation and enlargement of the stoma site to facilitate exteriorization of the bowel. The tail of the endoloop, after placement, is not cut but rather is tagged with a clamp and then, later, is grasped with a finger inserted via the stomal wound into the abdomen and then pulled into the stomal site. If possible the stoma is brought out off the midline and within the rectus muscle. The most difficult setting is that of carcinomatosis where both the small and large bowel may be attached or adhesed to metastases in the bowel, mesentery, abdominal wall, or retroperitoneum. These attachments may greatly limit the mobility of the bowel and may force the surgeon to exteriorize a less than ideal bowel segment (usually more proximal than desired) or use a midline, subcostal, or very low location for the stoma. Abdominal wall metastases also make placement of ports a challenge and, possibly, dangerous. The surgeon is best off doing a cut down and placing a Hassan type port under direct visualization when carcinomatosis is suspected or if the patient has had multiple prior operations.
It is advised that tumoricidal irrigation be carried out at the end of any operation done for a patient with Stage 4 disease. The following agents have been evaluated in small animal studies: 5 Fluorouracil, heparin, taurolidine (0.2% solution), and poviodine. All of these agents have been shown to decrease intrabdominal and/or incisional tumor formation in the rodent setting.(7,8) The authors laboratory has shown that betadine was effective in decreasing the incidence of port and incisional tumors in a splenic tumor model.(9) In the human setting, to the authors knowledge, a dilute betadine solution is the most commonly employed method. The author routinely performs irrigation with a dilute poviodine solution (100 cc of the standard poviodine solution [which is a 10% solution] is added to 1000 cc of saline) in patients with Stage 4 disease. The abdomen is filled with the dilute solution and left for 2 minutes, after which the abdomen is suctioned and then irrigated again with plain saline (x 2 liters). The poviodine when used full strength and when left in the abdomen at the case’s end has been reported to rarely cause adhesions and has been associated with an arrhythmia. Unfortunately, the poviodine does kill peritoneal macrophages as well as tumor cells. It is judged that killing the residual viable tumor cells in the abdomen is of greater benefit than the maintenance of the macrophage population. As of several years ago, in Germany and several other parts of Europe taurolidine was being assessed in a clinical study as a tumoricidal irrigation agent by Dr. C Jacobi.
1. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, Cancer J Clin 2002;55:74-108.
2. Kumara HM, Feingold D, Kalady M, et al. Colorectal resection is associated with persistent proangiogenic plasma protein changes: postoperative plasma stimulates in vitro endothelial cell growth, migration, and invasion. Ann Surg. 2009 Jun;249(6):973-7.
3. Scheidbach H, Schubert D, Hugel O, et al. Results of laparoscopic surgery for colorectal cancer in palliative intent. Surg Laparosc Endosc Percut Tech 2007;17:79- 82.
4. Fukunaga Y, Higashino M, Tanimura S, et al. Laparoscopic surgery for stage IV colorectal cancer. Surg Endosc DOI 10.1007/s00464-00900778-7.
5. Moloo H, Bedard ELR, Poulin EC, et al. Palliative laparoscopic resection for Stage IV colorectal cancer. Dis Colon Rectum 2006;49:1-5.
6. Gonzalez R, Smith CD, Ritter EM, et al. Laparoscopic palliative surgery for complicated colorectal cancer. Surg Endosc 2005;19:43-46.
7. Neuhaus SJ, Watson DI, Ellis T, et al. Influence of cytotoxic agents on intraperitoneal tumor implantation after laparoscopy. Dis Colon Rectum. 1999 Jan;42(1):10-5. 118
8. Braumann C, Jacobi CA, Rogalla S, Menenakos C, Fuehrer K, Trefzer U, Hofmann M. The tumor suppressive reagent taurolidine inhibits growth of malignant melanoma–a mouse model. J Surg Res. 2007 Dec;143(2):372-8.
9. Lee S, Gleason N, Bessler M, et al. Peritoneal irrigation with providone-iodine after laparoscopic-assisted splenectomy significantly decreases port-tumor recurrence in a murine model. Dis Colon Rectum. 1999 Mar; 42(3)”319-26.