Loco-regional advanced colorectal cancer: diagnostic and therapeutic features

Introduction
Colorectal cancer represents the most frequent site of digestive neoplasic disease, with a continuously increasing number of cases; the importance of study results from the highly number of cases discovered in advanced stages of disease (stage B, C or D in MAC system). (1, 2)
Advanced colorectal cancers are represented by those cases in which the tumors penetrate beyond colorectal outer layers, cancers with nodal involvement (stage C), distant metastatic disease (stage D) and/or recurrent disease (locally or distant recurrences). (3, 4)
This paper's aim is to analyze the main diagnostic and therapeutic problems regarding the loco-regional advanced cases.

Methods
This retrospective study includes all patients diagnosed and operated on in 2nd Surgical Clinic of Craiova's Emergency Hospital, for a 5 years period (2001-2005); there were 224 patients with advanced colorectal cancers out of 254 cases of colorectal cancer operated on this period.
Out of these advanced cases there were 44 cases (19.64%) with locally advanced disease (T3N0 or T4N0 - Dukes B stage), 72 cases (32.14%) with histological confirmed nodal involvement (Dukes C), 39 cases (17.41%) with insufficient number of lymph nodes histologicaly examined (less than 12 lymph nodes examined) (T3 or T4NxM0) and 69 cases (30.8%) with distant metastasis (D stage).
Patient's age analysis reveals a large range of distribution, between 28 and 91 years old, with an average of 64 years; the peak of distribution is between 50-70 years, with 129 cases (57.6%).
Clinical characteristics analysis revealed that 72 cases (32.14%) had an acute onset: intestinal obstruction in 63 cases (28.125%); peritonitis in 5 cases (2.23%), 3 peritonitis by tumoral perforation and 2 by diastatic perforation; massive tumor bleeding in 2 cases (0.89%); ceco-ascendent intussusceptions due to cecal tumor in 1 case and abdominal parietal abscess (necrotizing parietal fasciitis) in 1 case.
There was an important associated pathology, represented by cardio-vascular diseases - 77 cases (34.37%), respiratory illness - 26 cases (11.6%), urinary associated disease - 26 cases (11.6%), diabetes mellitus - 29 cases (12.94%), cerebro-vascular stroke - 9 cases (4%); this situation had a serious impact on the type of operation we have performed and, obviously, on patients postoperative evolution.
Tumor topography on the large bowel level was right colon in 66 cases, transverse colon in 7 cases, left colon in 75 cases, rectosigmoid junction in 12 cases and rectal topography in 63 cases. Most cancers were colorectal adenocarcinoma (197 cases - 87.9%); mucinos structure of tumor was presented in 24 cases (10.71%) plus 2 cases of signet ring cell adenocarcinoma.
Histological evaluation of lymph nodes showed that only in 69 (30.8%) cases were examined a sufficient number of lymph nodes (12 or more) for correct staging of disease, while in 12 cases no lymph node was examined (5.35%).
Surgery was the main therapeutic methods in all cases; for the right colon cancer were done 55 right hemicolectomies, with 6 extended resections of adjacent organs, 9 internal by-passes (ileo-transvers anastomosis) and exploratory laparotomy in 2 cases. For obstructive tumors the resection was performed primarily in only 17 cases (26.98%), in rest specific emergency condition leading to serial operations.
For transverse colon cancer the following surgical procedures were practiced: 4 Toupet colectomies, 2 extended with partial gastrectomies; 1 right hemicolectomy extended to the left colon; 1 internal by-pass (cecosigmoidostomy) and 1 exploratory laparotomy. For left colon cancer there have been practiced: 14 left hemicolectomies; 23 left atypical colectomies; 16 Raybard colectomies; 7 subtotal colectomies plus 1 total colectomy; internal by-pass or supratumoral colostomy in 11 cases and exploratory laparotomy in 3 cases. In rectal and rectosigmoid cancer it was possible to perform 23 Dixon procedures, 18 Miles procedures, 16 Hartmann's procedures, 1 internal by-pass (ileorectostomy) and 17 supratumoral external colostomies.
The extended resections included as adjacent invaded organs: 1 cholecistectomy; 1 atypic hepatectomy; duodenal partial resection in 1 case (followed by transverse suture); 2 partial gastrectomies; 4 enterectomies; 1 splenopancreatectomy; 2 splenectomies; 2 nefrectomies; 3 partial cistectomies; 2 histerectomies and other 2 partial colpectomies; 1 partial prostatectomy. Partial parietectomies for invaded abdominal wall (anterior or posterior) were necessary to perform in 7 cases. There was necessary to perform extended resections in 12.94% of cases (29 cases).
Neoadjuvant radiotherapy was applied in 29 cases of middle or lower rectal cancer, with no results in 4 cases; all patients were guided to oncology for adjuvant chemo/radiotherapy.

Results
Tumor resecability was possible in 79.9% of all cases, in 64.4 % of these cases the procedures having radical extent.
In this lot of patients 16 deaths were recorded (7.14% mortality rate), 13 deaths being recorded after emergency surgery.
The main causes of death was general conditions, in 12 cases (myocardial infarction in 6 cases, pulmonary embolism in 3 cases, bronchopneumonitis in 2 cases and cerebrovascular stroke in 1 case). Related to surgery causes of death were abdominal sepsis, leading to MODS in 3 cases and inoperable intestinal obstruction (peritoneal carcinomatousis) in 1 case.
Postoperative global morbidity was 33.92% of all cases (76 cases had one or more postoperative complications); most of them were general complications (50 cases): one cerebral vascular stroke; 7 deep venous thrombosis; 3 pulmonary embolism; 5 bronchopneumonitis; acute pulmonary edema in 1 case; myocardial infarction in 7 cases; urinary complications in 18 cases, including 1 uretheral stenosis and 1 acute renal failure; lower limb edema (vascular compression due pelvic tumor) in 2 cases and intravenous catheters associated phlebitis in 4 cases.
Abdominal complications were recorded in 32 cases: postoperative mechanical intestinal obstruction in 7 cases; postoperative progressive peritonitis in 2 cases; postoperative intraperitoneal abscesses in 5 cases; anastomotic leakage followed by external colic fistula in 16 cases (11.03%); 1 enteral fistula, after an extended resection included 2 ileum loops; intraperitoneal hemorrhage in 1 case.
Parietal complications were recorded in 29 cases: 23 wound infection, 1 case of necrotizing fasciitis and 5 cases of evisceration (1 free evisceration).
STOMA - related complications were present in 6 cases: retraction of bowel in the abdominal wall and severe parietal infections (1 case), peristomal evisceration of omentum (2 cases), necrosis of stomic bowel (1 case) and hemorrhage in exteriorized large bowel mesentery (2 cases).

Discussion
Despite the latest discoveries in cancer's molecular biology and modern examination techniques, difficulties in early diagnostic and correct staging of colorectal cancer are still encountered. These facts are reflected in a decreasing number of cases that may benefit from adjuvant therapy; moreover, problems in preoperative and even postoperative staging of cases lead to difficulties in adopting a correct and uniform therapeutic strategy of these cases, leading to poor results in the treatment of such patients. (5, 6)
Problems related to primary tumor
In the last 10-15 years new modern changes were registered in molecular biology and in preoperative exploratory techniques (colonoscopy, barium enema, virtual colonoscopy, endo-ultrasonography, MRI or CT), which allow us to detect early precancerous lesions, therefore to apply a prophylactic treatment of colorectal cancer. In spite of these remarkable discoveries an increased number of cases of colorectal cancer is still registered; moreover most of these cases are in advanced stages of disease (almost 90%), with severe complications (intestinal obstruction, tumor perforation - over 1/3 of cases!) which reduce the chance of a curative resection. These facts conclude that the only reliable methods to reduce the number of cases, and especially advanced cases of colorectal cancer, is to develop and apply a screening program, which allows to detect precancerous lesions and early colorectal cancer, treatable with very good results (1, 7, 8).
Regarding the improvement of the tumor-related staging techniques there were some advances: virtual colonoscopy, endoultrasonography, MRI or CT which allows more accurately predicting T stage, but never with 100% accuracy; the best methods remains exploratory laparotomy with biopsies from all surrounding peritumoral suspect tissue (7, 8).
In advanced cases to perform such biopsies may be difficult since the detachment of colorectal cancers of adjacent invaded organs is forbidden, because of the risk of tumor dissemination; in this matter there are some studies who suggest that en block resection is better for the patient, even if the adjacent organs are really invaded only in 40-60% of cases. Dissection of tumor from the invaded adjacent organs leads to an increased number of recurrences and a decreased chance for long distance therapeutic good results (9, 10, 11).
Surgery of primary advanced tumors
Dissimilar to other sites of neoplasic disorders, in colorectal cancer a B stage (or stage II in TNM classification system) represents a locally advanced disease, with a tumor already spread beyond the outer border of the organ, often invading the adjacent organs. This aspect correlates with an increased number of necessary extended resections; even so, there is a great risk of residual microscopic tumor (R1) or even macroscopic tumoral tissue (R2 resections) after the surgery (5, 12).
Nevertheless, many studies have shown that extended resections are beneficial to the patients, increasing the free disease survival intervals; it leads to prolonged distant survival and alleviates the patients' quality of life. Therefore we have practiced extended resections of adjacent involved organs whenever it was possible; in most cases those resected organs were urinary or genital organs, small bowel loops or partial parietal resections. (13, 14, 15) (fig. 1)
In advanced right colon cancer the most severe situations were the invasion of the right iliac pedicle (cecal cancer) or the hepatic pedicle (cancer of the hepatic flexure) both leading to inoperability.
In case of duodenal extension of an ascending colon cancer there is some debate about the optimal modality of solving the invasion; some authors claims that only pancreatoduodenectomy may be truly beneficial as curative treatment, while others sustain that a duodenal resection may be sufficient. The modalities of solving the duodenal defects vary from transverse suture to a duodenoplasty with a Roux-en-Y jejunal loop or even reconstruction with ileal flap (15, 16, 17, 18).
In such cases we practiced resection of invaded segment of duodenum followed by transverse suture (the defect was below 5 cm in diameter), with good postoperative results; in some cases invasion of duodenum leads to inoperability because of age, biologic altered status of the patient or too advanced disease (peritoneal stage IV) (fig. 2).

For left colon cancer the problems were similar, but the invasion of spleen or pancreatic tail was much simpler to be resolved by a splenopancreatectomy (Figure 3).
In both, left and right tumor topography, involvement of ureterus (left or right) can be resolved by en block resection with nephrectomy (it is mandatory to know the controlateral kidney functions) or ureteroplasty.
In rectal or sigmoid cancer the involvement of female genital organs can be simply resolved by en block resection (Figure 4), but the invasion of urinary tract (in mens or advanced tumor in female rectal cancers) leads to more difficult surgical problems. Invasion of bladder out of the trigonal area is possibly to be solved by a partial cistectomy with cistoraphy, but the invasion of the later area or the pelvic ureters may lead to a more aggressive surgery - pelvectomy (19, 20, 21) (Figure 5).
We have not performed yet pelvectomy in advanced primary colorectal cancers, but there are many studies who suggest that this aggressive type of surgery may be very useful to selected patients therefore this is an aspect for our future experience (12, 22).
In case of severe acute complications of colorectal cancer (especially hemorrhagic or perforated tumors) removal of the tumor is mandatory, but it is often made in an atypical manner (limited resection) in order to save the patient's life (2, 15).
In middle rectal cancers another problem is to preserve anal sphincter function, not always possible in advanced tumors, therefore an increased number of abdominoperineal resections are often necessary to be made (8, 15, 23, 24).

Lymph nodes involvement and advanced colorectal cancer
It is known that the tumor invading the outer muscular layer (T3 or T4) correlates with an increased percent of cases with lymph node involvement and a great number of lymph nodes susceptible to be invaded; therefore, surgery addressed to lymph nodes (lymphadenectomy) must be a constant preoccupation for the surgeon that operates a locally advanced colorectal cancer. The reasons are many: probably the most important is removal of all tumoral tissue, that increase the number of curative resections; if not possible, decreasing as much as possible of the tumoral mass (citoreductive surgery), allow the chemotherapy to be more efficient and leads to prolonged disease-free survival interval (25, 26).
Another reason for lymphadenectomy is that harvesting a great number of lymph nodes permits a more accurate staging (N1 or N2 stage); it has already been proved that histological analysis of 9 or more lymphatic nodules leads to a more accurate N staging, but also never infallible (there are still cases declared with non-nodal involvement - A or B stage - followed in a short period of time by the recurrence of disease, nodal or metastatic) (27, 28, 29).
This is mainly due to micrometastatic disease, undetectable with usual histological stains. More efficient seem to be molecular analysis to detect micrometastasis in the lymph nodes, associated with an increased number of lymph node histologically examined (30).
The main problem is that these modern techniques are not always available, so we have to do our best to harvest as much as possible from the lymph node that drain the tumor site, and analyze them at least histologicaly and whenever it is possible, imunohistochemicaly. Even so, we cannot predict 100% for sure the N stage of disease, therefore it is useful to perform lymphadenectomy in all cases that permit it (according to the patient's general and biological status).
Finally but not least, removal and histological analysis of many lymph nodes imply a better staging, therefore they permit to establish more accurately patient's prognosis, being known that long term survival decreases significantly for patients with lymph node metastasis (5, 25, 28).
Discussion over surgical results
Tumor resecability was lower in advanced cases (systemic or locoregional) but there is place for improvement, especially in locally advanced cases in which extended resection of adjacent organs can now be made safely for the patient, leading to a better local control of disease and some improvements in overall survival.
In advanced metastatic disease standard resections are always useful to the patient, but extended resections in such cases may be a point of debate, related to the possibilities of removing the metastasis and giving so the curative intent of surgery.
The morbidity after such surgical interventions is greater than morbidity after standard resection, but the mortality seems to be very likely in both situations; moreover, the mortality was determined especially by the general altered status of the patients, and appeared almost only in emergency operated cases (25).
The problem of neoadjuvant and adjuvant therapy
In locally advanced (T2, T3 or T4) stages of rectal cancer it was considered mandatory to use preoperative radiotherapy (except acute complications); now are debatable again if it is absolutely necessary in all these cases, because of its side effects. Therefore some studies have tried to establish the risk factors for recurrences and the best criteria to choose the suitable patients for this more aggressive strategy of treatment (31, 32).
A problem to be discussed is whether or not oncologic treatment after a laparotomy for an inoperable colorectal cancer may be followed in selected cases by curative surgery, being known that chemoradiotherapy is able to decrease the volume of primary tumor and even down-stage some cases (33, 34).
We have already succeeded in removing a primary inoperable rectal cancer after radio-chemotherapy in 2 cases, but we have not encountered the same situation in colon cancer; moreover, the number of cases is too small for permitting to conclude in this matter. There are also, no prospective studies to sustain this kind of approach therefore any attempt to perform curative surgery in such cases must be adapted to each case individually.

Conclusion
1. Colorectal cancer continues to represent a major surgical challenge because of its increasing incidence.
2. A great proportion of colorectal cancers are discovered in advanced stages of disease (almost 90% according to our statistics).
3. Emergency cases (acute intestinal obstruction, peritonitis) represent over 1/3 of cases; that leads to poor therapeutic results because of higher postoperative morbidity and mortality, impossibility to perform neoadjuvant treatment and a reduced number of curative resections.
4. Extended resections are often necessary, justified by improved results in distant survival, but correlates with a higher postoperative morbidity.
5. An improving of diagnosis and staging is still necessary to be made to diagnose more and more incipient lesions and to achieve better therapeutic results.

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