BJS, September, 5, 1999 BJ S C U R R E N T Ghassan A. Nasir* & Mazin H. Al-Hawaz@

C *FRCS Consultant Surgeon, Basrah General Hospital. @Arab Board Certified Surgeon, Assistant Professor of O Surgery, University of Basrah, College of Medicine & Specialist Surgeon Basrah General Hospital Basrah; IRAQ. N C E ne in 20 individuals is at risk for posis coli) gene. This gene is located P O developing colonerctal cancer. on chromosome 5 near q 21.22 T This risk is age dependent with almost locus1,3,4,5,6. an 18-fold increase after the age of 65. II-Hereditary non-polyposis colon can- In 1996 colorectal cancer affected cer (HNPCC). This is Lynch synd- 133.000 person in USA and 55000 died rome, which is of two types Lynch I of the disease. and Lynch II syndromes. The gene responsible for this syndrome is mapped to chromosome 2,3,4,5. Aetiology III-Other genes have been implicated in

colon cancer development. These are: The exact cause of colon and rectal 1-Myc on chromosome 8. cancer is not known but there are 2-K.ras on chromosome 12. inherited (genetic and familial) and 3-P & neu/ HER on chromosome 17. environmental1,2,3,4 (Dietary and others) 53 2 4-DCC on chromosome 18q. factors as well as certain preexisting K-ras, neu/HER2 and myc are known conditions have been implicated2,3,4. oncogenes. APC, DCC and P are 53 known suppressor genes1,3,4,5. A- The inherited factors

1-Some cases are caused by known B-Environmental factors genetics disorders e.g. (APC gene in These include the diet and other FAP syndrome) factors in the environment. 2-Other cases have very strong fami- Diet: the association of high fat, low lial tendecies e.g. (Lynch syndrome) fiber diet with colorectal cancer has long 3-Other cases related to specific pre been suspected, a sedentary life style, malignant disease such as ulcerative obesity and high level of dietary fat have colitis and Crohn’s disease3,4. been implicated as factors predisposing

to large bowel cancer1,3,4. Genetic predisposition 1-Fat is toxic to colonic mucosa, diet Genes play role in the development of rich in saturated and polyunsaturated colo-rectal cancer and 15% of cases of fats is carcinogenic to colorectal colo-rectal cancer are genetically pre- mucosa. disposed1,3,4,5. 2-Increased dietary fibers decreases the I-First observations are in the patients incidence of colorectal cancer due to with familial adenomatous polyposis rapid evacuation of diet, dilution of (FAP) syndrome. The syndrome is an dietary carcinogens and reduction of autosomal dominant. The gene respon- mucosal contacts to these carcinogens. sible is APC gene (adenomatous poly- 3-Bile acids and alcohol promote a Correspondence to: mutational changes in the colo-rectal Dr. Ghassan A. Nasir 3,4 P.O. Box 36, Basrah, IRAQ. mucosa .

134 Colorectal cancer G. Nasir & M. Al-Hawaz

Fearon and Vogelstein have proposed a for staging, treatment and prognosis of model for genetic changes leading to the disease. 4,5,7 colorectal cancer . *In spite of digital examination of anus and , pelvic examination under Deletion of APC Mutation of k- ras general anaesthesia is necessary espe- (Tumor suppressor Initiation of (proto-oncogen) on cially in female patients to evaluate the gene) on chromosome small polyps chromosome 12 5 tumor, its size, extent and fixity with epi or para rectal lymph nodes enlargement Large tumor Deletion of DCC (Tumor Growth of benign if present. growth suppressor gene) on polyp chromosome 18 *Fibreoptic which can identify and biopsy even small lesions Deletion of P53 Others genetic (<0.5 cm). However, in up to 10% of (Tumor suppressor changes gene) on chromosome carcinoma examination the proximal colon can not 17 1,3 be reached . Metastasis *Double contrast barium enema is necessary especially for those patients Diagnosis with colonoscopic failure also to evaluate the bowel proximal to the lesion Screening programme is used for early (synchronus tumors). detection of colo-rectal cancer in *Ultrasound to the abdomen, pelvis and patients with high risk factors for transrectal ultrasound in cases of rectal developing colo-rectal cancer, which cancer. includes: 1-digital examination for every *CT scan to the pelvis and abdomen person>40. *MRI to the pelvis, abdomen and 2-FOT (faecal occult test) for every transrectal MRI. person >50. 3-fibreoptic for every To determine the local extension of person > 50. tumor in cases of rectal and sigmoid 4-either colonoscopy or barium enema colon cancer, and that of the abdomen to (double contrast) for person with high determine para-aortic lymph node and risk factors. metastases. 5-serological tumor-markers are of no *Liver function test, alkaline phos- value now3,9. phatase, SGGT, SGOT, SGPT, LDH. Those patients with risk factors for *Chest x-ray colo-rectal cancer are: a-FAP and associated syndrome (Gar- To detect any metastasis. dner, Turcot’s). *Tumor markers b-longstanding pancolitis. c-longstanding left side colitis. CEA still remains the most widely d-HNPCC diagnostic marker for colorectal cancer. e-those with history of pelvic radiation. Despite discovery of other markers such f-those patients with uretero-sigmoido- as CA 19-9 or CA –50 or TAG-72 have stomy for urinary diversion3,4,9. not been widely accepted. There are a lot of measures to be done for diagnosis of colorectal cancer and to CEA 0-2.5ng/ml Normal see its local extension, lymphatic and CEA <10ng/ml Benign condition distant metastases which are necessary CEA >10ng/ml In colorectal cancer

135 Colorectal cancer G. Nasir & M. Al-Hawaz

*Immuno scintigraphy. Stage II T3, T4 No Mo Radio labeled antibody to target tumor. Stage III Any T Any N Mo Indolium 111 (In111)- labeled anti TAG Stage IV Any T Any N M1 72 for imaging colorectal cancer. Prevention9 *Urinary system evaluation by. IVU, radio opaque enhanced CT and This can be done by the following steps: cystoscopy. All these investigations aid to deter- 1-Periodic colonoscopy and polypec- tomy especially for high-risk patients. mine the following: I-The depth of tumor penetration into 2-Prophylactic or proctocole- bowel wall ctomy will be done in some cases of II-The involvement of regional lymph polyposis, and some cases of ulcerative nodes. colitis.

III-The presence of distant metastasis. 3-Sulindac is antiinflamatory drug, could decrease adenoma in colon polyposis Staging of colorectal cancer 1,3,4,8,9 syndrome and this decrease colorectal TNM staging is now usually cancer9. used. 4-NSAID and aspirin was found to 1)Primary tumor (T) reduce all forms of colorectal cancer 9 Tx-primary tumor can not be assessed. when was taken as prophylaxis . To-no evidence of primary tumor. Tis-carcinoma in situ. Treatment T1-tumor invades submucosa. T2-tumor invades muscularis properia. In patients with potentially curable T3-tumor invades subserosa., serosa., colorectal cancer, surgical resection is pericoloic or rectal fat. essential for optimal oncologic and T4-tumor invades the visceral periton- functional result. In majority of such ium and adjacent structures. cases en bloc resection of the primary tumor and regional lymph nodes is only 2)Regional lymph nodes (N) needed1,3,4,10. But for locally advance Nx-lymph nodes can not be assessed. disease (transmural or node positive) are No-no evidence of lymph nodes benefit from surgery and adjuvant metastasis chemoradiation therapy. Clinically tethe- N1-metastasis in 1-3 peri-colic or peri- red or fixed rectal cancer is treated with rectal lymph nodes. pre-operative radiation therapy, while N2-metastasis >4 peri-colic or peri- small rectal cancer may be cured with rectal lymph nodes. local excision alone if they are low grade N3-Metastasis in any lymph nodes on post operative pelvic radiation and along named vascular trunk. concurrent chemotherapy if they are high grade3,4,9,10,11. The modern surgical 3)Distant metastasis (M) approach to colorectal cancer must con- Mx-presence of distal metastasis can sider margins free of resection and en not be assessed. bloc resection of draining lymphatic Mo-no distant metastasis tissue. Almost 90% of patients have M1-distant metastasis. tumors that can be resected completely and the mortality rate 2-10%. After good The stage of TNM system is as follows: bowel preparation for the patients by Stage 0 Tis No Mo mechanical and chemical ways. The Stage I T1,T2 No Mo anatomical resections are as follow:

136 Colorectal cancer G. Nasir & M. Al-Hawaz

3-less than one quadrant of rectal cir- cumference involved. 1)Caecum and Right 4-mobile one. ascending colon. hemicolectomy. 5-well differentiated and no lympho- vascular or perineural invasion. 2)Hepatic flexture Extended right 6-endo-rectal u/s show that the tumor T1 and proximal hemicolectomy with or T2 No (no lymph nodes involved). transverse colon omentectomy. 7-CT no metastasis. 3)Distal transverse Either This local excision done by one of colon and splenic I-extended right these procedures: flexture. hemicolectomy to a-transanal excision. descending colon. b-transcoccygeal excision (Kraske). Or II Left c-transsphincteric excision (York-Ma- hemicolectomy with son). omentectomy. d-transanal endoscopic micro surgery (TEM)10,12. 4)Descending colon Left hemicolectomy Although a 1 cm margin is ideal but 0.5 and sigmoid. with sigmoid cm margin of grossly normal mucosa colectomy. beyond the edge of the tumor is more realistic. A full thickness rectal wall 5)Upper and middle Upper or lower excision to the level of perirectal fat is third rectum. anterior resection required. The wound is irrigated and with coloanal anas- closed. A transmural extension (T3) are tomosis. major risk factors for local recurrence, so requires postoperative chemo- 6)Lower third rec- Abdomino-perineal radiation therapy. The major advantage tum resection. of local excision is avoiding , avoiding longer period of pain and Well-differentiated rectal cancer req- avoiding urinary, sexual and wound uires distal margin of 2cm as adequate complication of lower anterior resection margin clearance, while poorly differen- (LAR)10,11. tiated rectal cancer requires 5 cm distal margin clearance. Laparoscopic colectomy10,14,15,16 *Since the advent of circular stapling device in 1970s. However, the double- Because of technological advances and stapled technique developed by Knight the overwhelming success of laparo- and Griffen in 1980s is most frequently scopic technology in abdominal opera- used in creating distal anastomosis after tions, laparoscopic colectomy has been resection of low lying rectal cancer10. used in management of colorectal **Some have implemented construction cancer. Right and left colon, sigmoid of colon J Pouch to produce neorectal colon and upper rectum are the most resrvoir in order to reduce the stool frequent part to be resected by laparo- frequency10. scope, while other parts of colon are ***Local excision of rectal cancer invo- difficult to be resected because of lves removing the tumor in its entirely in omental attachment. The benefit of lapa- addition to margins of surrounding nor- roscopically assisted colectomy are: mal tissue. The success of this operation 1-reduces postoperative pain and ileus. depends on criteria of the tumor as: 2-early tolerance of feeding. 1-less than 4 cm in diameter. 3-shorten hospital stays. 2-within 6-8cm from anal verge. 4-less operative blood loss.

137 Colorectal cancer G. Nasir & M. Al-Hawaz

5-improve cosmesis. colonoscope with or without sadation. The disadvantages of these procedures For low type rectal carcinoma this are: SEMS must not be used because the a-longer operative period. patient can not tolerate it and there is a b-expensive equipment. feeling of tenesmus all the time. It is c-additional surgeons. better to do balloon dilatation or laser 17 d-implication of Co2 insufflation which recanalization . may lead to spread of malignancy. e-there is a danger of local recurrence of Adjuvant treatment for colorectal malignancy which is due to : cancer2,3,4 1-contamination of wound by tumor cells. It is clear now that curative surgery 2-increase exfoliation of tumor cells by alone is not sufficient for patients with laparoscopic technique and manipula- increase risk of recurrence after surgery. tion. Those patients are: 3-pneumo-peritonium effect on tumor 1)stage II colorectal cancer with elevated cells attachment and growth15. CEA pre-operatively. There is no special criteria for choosing 2)stage III colorectal cancer. patients to laparoscopic colectomy, but So those patients requires adjuvant the following points are considered: therapy (chemical, immunological, rad- I-thin. iotherapy and hormonal therapy). II- no previous adbominal surgery. III-patients with no coagulopathy, I-Adjuvant chemical therapy liver, respiratory and cardiac disease. Those are 5-Fluorouracil (5 FU.), leva- IV-advance colorectal disease such as misole, leucovorin, and interferon. They perforation, obstruction and colo- are given alone or in combination, they vesciral fistula. improve overall and disease free survival Laparoscopic colectomy may be (DFS). Levamisole is an antihelmintic converted to laparotomy if there are agent that enhances 5FU’s toxicity to unclear anatomy, adhesion, abscesses, human colon cancer cell lives, but its bleeding and technical difficulties. As exact mechanism of action is unknown2, we mentioned before right hemi- it may: colectomy, sigmoid colectomy, high a-inhibit tyrosine phosphatases in tumor anterior resection and stoma formation cells. are the procedures that can be performed b-enhance natural-killer lymphocyte by a laparoscope. activity. c-induce expresion of HLA, molecule in Palliative treatment cancer cell. d-claimed immunomodulatory effect The poor condition of some patients (non specific active immunothera- with acute malignant obstruction of the py)18. left colon or irresectable advance pelvic disease make the performance of colo- stomy the only reasonable and un- II-Adjuvant immunotherapy3,4,18,19,20 avoidable technique17. But recently one These are: can use the self-expanding metal stent 1-tumor targeting monoclonal anti- (SEMS) to relieve colorectal malignant bodies (MoAb). obstruction as a palliative measure in 2-auto logous tumor vaccine. patients with advanced colorectal malig- 3-expanded cytotoxic T.cells with cyto- nancies. This can be done through a kines administration.

138 Colorectal cancer G. Nasir & M. Al-Hawaz

1-Tumor targeting monoclonal anti- a-radiation to the bed of colon and rectal bodies cancer to reduce the post operative Two categories of antigen are present recurrence. on the surface of colorectal cancer cells. b-radiation is used in complicated colo- a-tumor associated antigen.(TAA) rectal cancer like perforation or b-tumor-specific antigen. (TSA)20 obstruction. c-radiation is used in patients with tumor The (TAA) includes the following anti- containing margin in the lymphatics or gens C6-17.1A, TAG 72, CA19-9, CEA, at the tangential margin of resection. L6, and 28A32. Monoclonal anti-bodies Radiotherapy may be given pre- (MoAbs) are developed against these operatively, post-operatively and in (TAA) and all are of mouse origin combination of the two known as except 28A32, which is human IgM. The sandwich technique. In theory, adminis- mechanism of these antibodies-mediated tration of pre-operative radiation therapy tumor cell cytotoxicties are: is better than post operative one because -antibody dependant cellular cytotoxicity undisturbed oxygenated tissue are more (ADCC). susceptible to ionizing radiation than the -complement dependent cytotoxicity vascular planes created by operation9. In (CDC). rectal cancer, radiotherapy is used pre- -antiiodo type response19. operative either by external radiation or endocavity radiation (through the anus). 2-autologous tumor vaccine The following regime is used: Active specific immunization were used in colo-rectal cancer. I-suspected transmural 2000 cGy external invasion. (non fixed, radiation for 5 days a-neurominidase-modified autologous well differentiated then surgical tumor cells and BCG. cancer) resection in the next b-autologous tumor cells modified by week. New Castle disease virus. These produce cell-mediated antitumor II-suspected trans- 4500 cGy external immunity3,18,20. mural invasion (fixed, radiation for 5 weeks poor differentiated 5 days/week), wait 3-administration of expanded cytotoxic cancer). for 6-7 week T.cells with cytokenis +reevaluation IL2 (inter leukin-2) which is lympho- +resection. kine before. LAK cell (lymphokine-activated killer III-poor operative 4500 cGy external cells). risk or extensive radiation for 5 weeks. IL2 was found to be solely responsible metastatic disease. reevaluation endocavitory for generation of LAK cell phenomenon. radiation 6000 cGy This phenomenon result in activation of for 2 weeks or macrophages and tumor killer cells surgical resection. result in regression of tumor cells, and reduction of tumor outgrowth and pro- *We wait for 6-7 weeks after external long survival over controls18. Injection radiation before surgery because: of IL2 alone or in combination of LAK a-to allow maximum tumor shrinkage. cells and IL2. b-to allow the acute inflammatory changes of radiation to subside. III-Adjuvant radiotherapy c-to allow the surgery to be perform Radiotherapy is limited in colon cancer before the chronic fibrotic changes of but it used in rectal cancer. radiation occur4.

139 Colorectal cancer G. Nasir & M. Al-Hawaz

IV -Adjuvant oophorectomy9 Co. 1997; 1020-1031. Bilateral oophorectomy is recommen- 10. Guillem JG, Paty PB. Cohen A.M. ded in all post menopausal women with Surgical treatment of colo-rectal carcinoma of the colon to decrease the cancer, CA CANCER J Clin 1997; 47: morbidity of neoplastic changes, while 113-128. in pre-mcnopausal women, this pro- 11. Breen E, Blady R. Preservation of cedure is only done if there is ovarian anus in the therapy of distal rectal abnormalities or in the presence of cancers. Surg Clin N Am 1997; 77(1): peritoneal implants9. 71-81. 12. Saclarides TJ. Transanal endoscopic References microsurgery. Surg Clin N Am 1997; 77(1): 229-239. 1. Arenas RB, Micelassi F. Colonorectal 13. Paik PS, Beart RW. Laparoscopic cancer, Current Surgical Therapy. Fifth colectomy. Surg Clin N Am 1997; edition, 1995. 77(1): 1-13. 2. Diazcanton EA, Pazdor R. Adjuvant 14. Ortega AE, Beart RW. Laparoscopic medical therapy for colorectal cancer. colon resection, JL Cameron. Current Surg Clin N Am 1997; 77(1): 211-225. Surgical Therapy. 5th ed. Mosby, 1995; 3. Chang HR, Bland KI. Tumor of the 160 -13. colon, MJ Zinner, SI Schwarts, H Ellis. 15. Jones DB, Guo LW, Reinhord MK. Maingot’s Abdominal Surgery 10th Impact of pneumoperitonium trocar edition. A. Simson & Schuster Co. site implantation of colon cancer. Dis 1997: 1281-1301. Colon and Rectum 1995; 38: 1182-1188. 4. Kodman IJ. Rectal cancer, MJ Zinner, 16. Abel ME. What’s new in colon and SI Schwarts, H Ellis. Maingot’s rectal surgery. J Am Coll of Surgs Abdominal Surgery 10th edition, A. 1996; 182: 89-92. Simson & Schuster Co. 1997: 1455-1501. 17. Fuentes FT, Belda AE, et al. Trans- 5. Howe JR, Guillen JC. The genetic of anal self expanding metal stents as an colorectal cancer. Surg Clin N Am alternative to palliative in 1997; 77(1): 175-191. selected patients with malignant obst- 6. Clark, SK, Phillips RK. Desmoid in ruction of the left colon. Br S J 1998; familial adenomatous polyposis. Br J S 85: 232-235. 1996; 83: 1494-1504. 18. Etting Hausen SE, Rosenberg SA. 7. Fearon ER, Vogelstein B. Agentic Immune and gene therapy of cancer, model colorectal tumorigenesis, Cell advances in surgery. JL Cameron, CM 1990; 61: 759-767. Balch, B Langer, Mosby. 1995; 28: 8. Scott.Conner CE, Christie DW. 223-245. Cancer staging using AJCC TNM 19. Pullyblank AM, Manson RT., Mono- system. J of Am Coll of Surgs 1995; clonal antibody treatment of colo-rectal 81: 182-188. cancer, Br S J 1997; 84: 1511-1517. 9. Kim Lyerly H. Carcinoma of the 20. Armstrong CAM, Durrant LG, Scho- colon, rectum and anus, Sabiston text- lefield JH. Colorectal cancer vaccine, book of surgery, 15th edition. Sanders Br S J 1998; 85: 149-154.

140 Colorectal cancer G. Nasir & M. Al-Hawaz