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Carcinoma colon-and-management

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Carcinoma colon-and-management

  1. 1. CARCINOMA COLON AND IT’S MANAGEMENT Dr. SHIV KISHOR Moderator: Dr. H.S KHETARPAL DR HARPAL, DR SANJEEV
  2. 2. INTRODUCTION • 2nd commonest cancer in men and ranks 3rd in frequency in women in the western countries • 2nd m/c cause of cancer mortality (after Ca Lung) • Incidence : 35.8/100,000 (USA) • Developing countries < 10/100,000 • India: incidence - 7/1,00,000 • Median age of diagnosis- 62 yrs • Unfavorable prognosis if age <40 yrs SOURCE: RRCR 2007
  3. 3. CLINICAL ANATOMY • Large intestine- Colon and Rectum • Intraperitoneal- Caecum, Transverse colon • Retroperitoneal- Ascending colon, Descending colon, both flexures, initial part and end of Sigmoid • Significance – May have compromised sx margins – Tumor spread from these regions may involve retroperitoneal soft tissue, kidneys, ureters and pancreas • Cancer <12 cm anal verge – rectal cancer • Cancer >12 cm anal verge – colon cancer
  4. 4. Ascending Colon 4% Transverse Colon 8% Descending Colon 14% Sigmoid Colon 35.7% Rectum 39%
  5. 5. CLINICAL RISK FACTORS• Age > 40yrs • Male sex • Genetic syndromes- PJS/FAP/Gardener’s/Turcot • F/H- Lynch-I : Familial CRC syndrome Lynch-II : Hereditary adenocarcinomatosis synd. • Other – Prior h/o CRC /Malignant colorectal polyps – Inflammatory bowel disease – High BMI / Low physical activity – Red meat / processed food/ ? Low fiber diet – Excessive alcohol consumption/ low folate intake – Prolonged cigarette smoking – Pelvic irradiation
  6. 6. Adenoma carcinoma sequence Peak incidence for discovery of benign colorectal polyp is 50 yrs an development of colorectal cancer is 60yrs:  s/o 10 yrs span for progression of adenomatous polyp to cancer
  7. 7. CARCINOGENESIS: Adenoma to Carcinoma Pathway APC Loss/mutation Ch. 5q Normal Epithelium Early Adenoma Cancer Hyper- proliferation Intermediate Adenoma Late Adenoma K-ras Mutation Ch. 12p (50%) DCC loss Ch. 18q DPC4 Ch. 4 p53 Loss Ch. 17p Loss of DNA methylation
  8. 8. Colon Polyps • The term polyp of the colon refers to a protuberance into the lumen from the normally flat colonic mucosa. • Polyps are usually asymptomatic but may ulcerate and bleed, cause tenesmus if in the rectum, and, when very large, produce intestinal obstruction.
  9. 9. CLASSIFICATION • Neoplastic (adenomas and carcinomas), • Hamartomatous, • Non-neoplastic, and • Submucosal (neoplastic / non-neoplastic).
  10. 10. Non-neoplastic polyps • Hyperplastic • Mucosal • Inflammatory pseudopolyps • Submucosal
  11. 11. Synchronous lesion • An adenoma that is diagnosed at the same time as an index colorectal neoplasm is called a synchronous lesion. • Thirty to 50 percent of colons with one adenoma will contain at least one other synchronous adenoma.
  12. 12. Metachronous lesion • One that is diagnosed at least six months later is considered metachronous lesion
  13. 13. Pathologic classification • The histologic features and size of colonic adenomas are the major determinants of their malignant potential. • The glandular architecture of adenomas is characterized as tubular, villous, or a mixture of the two.
  14. 14. Tubular adenomas • Tubular adenomas account for more than 80 percent of colonic adenomas. • They are characterized by a network of branching adenomatous epithelium. • To be classified as tubular, the adenoma should have a tubular component of at least 75 percent
  15. 15. Villous adenomas • Villous adenomas account for 5 to 15 percent of adenomas. • They are characterized by glands that are long and extend straight down from the surface to the center of the polyp. • To be classified as villous, the adenoma should have a villous component of at least 75 percent.
  16. 16. Tubulovillous adenomas • Tubulovillous adenomas account for 5 to 15 percent of adenomas. • Have 26 to 75 percent villous component.
  17. 17. Polyp base • Sessile - base is attached to the colon wall, • Pedunculated if a mucosal stalk is interposed between the polyp and the wall. • Adenomas are most commonly found within raised lesions, up to 27 to 36 percent are flat (having a height less than one-half the diameter of the lesion) and up to 1 percent are depressed
  18. 18. Dysplasia • All adenomas are dysplastic. • A new system that recognizes two grades of dysplasia - HIGH and LOW. • Similarly, the older terms "carcinoma in situ" or "intramucosal adenocarcinoma" should both be described as high-grade dysplasia
  19. 19. Risk factors for focal cancer within an individual adenoma • Villous histology, • Increasing polyp size, • High-grade dysplasia
  20. 20. Polyp size & advanced features • The proportion of adenomas showing advanced histologic features (high-grade dysplasia or >25 percent villous histology) increases from • – 1 % in small adenomas (<5 mm) to – 7 to 12 % for medium-sized adenomas (5 to 10 mm) – 20 % for large adenomas (>1 cm)
  21. 21.  POLYPS WITH LARGER MASS HAVE GREATER VOLUME OF NEOPLASTIC CELLS ,HENCE A HIGHER LIKELIYHOOD OF HARBORING CANCER. POLYP SIZE(mm) <5 6-15 16-25 16-36 37-42 >42 NUMBER 5137 3581 1069 516 219 677 % WITH INVASIVE CARCINOMA 0 2.2 18.6 42.8 63.9 78.9
  22. 22. Age & advanced features • Older age is also associated with high-grade dysplasia within an adenoma, independent of size and histology
  23. 23. Advanced pathologic risk factors • Adenomatous polyps >1 cm in diameter • Adenomatous polyps with high-grade dysplasia • Adenomatous polyps with >25 percent villous histology • Adenomatous polyps with invasive cancer
  24. 24. Haggits and colleagues have proposed classification for polyps containing cancer acc to depth of invasion as: Level 0: Carcinoma does not invade the muscularis mucosa (ca –in-situ) Level 1: carcinoma invades head of pedunculated polyp(invades through muscularis mucosae) Level 2:invasion into neck Level 3:invasion into stalk Level 4:invasion into base.(invades submucosa) By defination ,all sessile polyps with invasive carcinoma are level 4.
  25. 25. Depth of submucosal invasion in sessile malignant polyps. Sm1: invasion into upper third Sm2: invasion into middle third Sm3:invasion into lower third.
  26. 26. Polyposis syndromes  Familial adenomatous polyposis (FAP). -Gardner syndrome. -Turcot syndrome.  Hereditary nonpolyposis colorectal cancer (HNPCC).  Peutz-Jeghers syndrome.  Juvenile polyposis syndome.  Cowden disease.  Hyperplastic polyposis syndrome.  Cronkite-Canada syndrome.  Bannayan-Riley-Ruvalcaba Syndrome.
  27. 27. Polyposis syndromes
  28. 28. 1.Familial adenomatous polyposis (FAP) Prototypical hereditary polyposis syndrome. Autosomal dominant. Frequency about 1:10,000. Account for about 1% of all colorectal cancers.
  29. 29. The APC gene: The adenomatous polyposis coli (APC) gene is a tumour suppressor gene located on chromosome 5q21.  Mutation in APC gene is genetic basis attributed to a truncating mutation in the germ-line APC gene. The gene expression is 100% in patients with the mutation. GENETICS
  30. 30.  The presentation and severity of disease is related to the site of the APC gene mutation.  Proximal APC mutations (proximal to codon 1249) produce a milder attenuated phenotype with sparse polyposis.  APC mutations between codons 1250 and 1330 present with tremendous degrees of polyposis.
  31. 31.  APC is universally expressed but mRNA is found in particularly high levels in normal colonic mucosa  Weighs 300-KDa: found in cytoplasm  APC binds and down regulates cytoplasmic b-catenin, preventing its translocation to nucleus.  Abnormal APC protein fails to do this, so that b-catenin is free to enter the nucleus and form a complex which results in specific transcription of cell cycle stimulating DNA sequences, and hence proliferation. The APC protein
  32. 32. Common expression of syndrome is:  Multiple colonic polyps(>100)  Polyps start after age 10–20, cancer in 100% at age 40. All patients will develop cancer of colon if left untreated.
  33. 33. Extra colonic manifestations
  34. 34. Gastric polyp :mostly are fundic gland hyperplasia and have limited malignant potential. Duodenal polyp: adenomatous thus premalignant. Duodenal cancer and desmoid disease are major sources of morbidity and mortality. Increased risk of adenocarcinoma in the periampullary region in 3–10% of patients
  35. 35. Interesting marker is CHRPE( congenital hypertrophy of retinal pigment cells). It is a patchy fundus discoloration. Detected by indirect ophthalmoscopy in 75% of patients.
  36. 36. Polyposis syndromes recognized to belong to general disorder of FAP include  Gardners syndrome.  Turcots syndrome.
  37. 37. Gardner syndrome (GS) Characterized by Colonic adenomatous polyposis  Osteomas: usually present in skull, mandible, and tibia –They are virtually always benign. Soft tissue tumours like epidermoid cysts, fibromas, desmoid tumors.
  38. 38.  Desmoid tumors can present in the retroperitoneum and abdominal wall of affected patients  These tumors seldom metastasize but are often locally invasive, and direct invasion of the mesenteric vessels, ureters, or walls of the small intestine can result in death.
  39. 39. Extra oral osteomas
  40. 40. Turcot syndrome Includes polyps Medulloblastoma Congenital hypertrophy of the retinal pigmented epithelium [CHRPE] Glioblastoma multiforme.
  41. 41. MYH POLYPOSIS An autosomal recessive form of FAP. Caused by mutation in the MutY homolog (MYH) gene. Individuals have fewer than 100 polyps Colonic microadenomas and duodenal adenomas are present. Diagnosis is considered in families where No APC mutation have been identified The mode of inheritance is not clearly autosomal dominant Polyp numbers are low.
  42. 42. Attenuated familial adenomatous polyposis (AFAP). Approximately 25% of FAP patients remain without an identified APC mutation Have lower polyp number(1-50) Later age at diagnosis Tendency to spare the rectum. Lower extra colonic manifestations.
  43. 43. Diagnosis Genetic testing: DNA from an individual with FAP is analysed to identify a mutation in APC, which is successful in about 80% of cases. Failure to detect an APC mutation does not exclude a diagnosis of FAP, and may occur for a variety of reasons including gene deletion AND some missense mutation.
  44. 44. Surveillance  Colonoscopy every 12 months starting at around age 10 to 12 and continuing until age 35 to 40 if negative.  Flexible proctosigmoidoscopy at age 10-12 year; repeat every 1-2 yr until age 35; after age 35 repeat every 3 yr  Upper GI endoscopy every 1-3 yr starting when polyps first identified
  45. 45. Familial Adenomatous Polyposis (FAP) SCREENING RECOMMENDATIONS Colorectal cancer 100% Colonoscopy annually, beginning age 10-12 yr Duodenal or periampullary cancer 5%-10% Upper GI endoscopy every 1-3 yr, beginning age 20-25 yr Pancreatic cancer 2% Possible periodic abdominal ultrasound Thyroid cancer 2% Annual thyroid examination Gastric cancer <1% Upper GI endoscopy as for duodenal and periampullary Central nervous system cancer <1% Annual physical examination
  46. 46. Management of large bowel  Once FAP has been diagnosed, the aim is to perform prophylactic surgery  Patients with severe polyposis or those people who are symptomatic, should have surgery as soon as possible.  In those individuals with milder disease, it can usually be delayed.  In these circumstances, annual colonoscopy is recommended to monitor disease.
  47. 47. Choice of operation The surgical options for the management of this condition are  Proctocolectomy with end ileostomy (with or without ileal pouch)  Colectomy with ileoanal anastamosis Proctocolectomy with ileal pouch anal anastamosis (IPAA).
  48. 48. Because ONLY few patients desire a permanent ileostomy, proctocolectomy with end ileostomy is rarely done. In most cases, however, the choice is between colectomy with IRA or proctocolectomy with ileoanal pouch (IPAA) . Surgical treatment of patients with FAP is directed at removal of all affected colonic and rectal mucosa.
  49. 49.  Restorative proctocolectomy with IPAA has become the most commonly recommended operation.  The procedure is usually accompanied by a distal rectal mucosectomy to ensure that all premalignant colonic mucosa is removed, and the IPAA is fashioned between the ileal pouch and the dentate line of the anal canal.
  50. 50.  An alternative approach is total abdominal colectomy with ileorectal anastomosis: has certain advantages.  Technically a simpler operation to perform  Pelvic dissection is avoided.  Theoretically less risk for anastomotic leak from the relatively simple ileorectal anastomosis  An additional argument : sulindac and celecoxib have been observed to cause the regression of adenomatous polyps in some patients with FAP.  The disadvantages are that the rectum remains at high risk for the formation of new precancerous polyps 12-29% after 20-25 years
  51. 51. Patients with Gardner syndrome require surgical treatment of  Cutaneous cysts  Symptomatic dental anomalies and osteomas  Biopsy and resection for malignancies, including hepatoblastoma, thyroid carcinoma, osteocarcinoma, gastric carcinoma, periampullary carcinoma, and biliary tract carcinoma  Liver transplantation may be required in patients with hepatoblastoma
  52. 52. Patients with Turcot syndrome require surgical intervention for diagnosis and management of CNS lesions, gastric lesions and hepatic lesions
  53. 53. Postop surveillance After IRA, the retained rectum should be examined using a flexible sigmoidoscope, every 6–12 months. Polyps larger than 5 mm should be removed If severe dysplasia or uncontrolled polyposis develops, completion proctectomy with or without ileoanal pouch formation is indicated. In patients who have had IPAA, the pouch should be examined by flexible endoscopy annually, and a careful digital examination of the anorectal transition zone should be performed.
  54. 54. Chemoprevention Have reduced the number and size of colorectal adenomas THESE ARE i. (NSAID) –sulindac ii.The COX-2 inhibitor celecoxib
  55. 55. 2.Hereditary non-polyposis colon cancer (HNPCC) HNPCC is the most frequently occurring hereditary colorectal cancer syndrome Autosomal dominant.  It also known as Lynch I and II syndromes. The Lynch I variants describe patients with predominantly colorectal cancer at a young age Lynch II: those with both colorectal and extracolonic cancers.
  56. 56.  Mutations in Mismatch repair genes (MMR ) result in the HNPCC syndrome (including hMLH1, hMSH2, hMSH3, hPMS1, hPMS2, and hMSH6)  Mutations in hMSH2 or hMLH1 account for more than 90% of cases.
  57. 57. These mutations produce microsatellite instability which result in errors in S phase when DNA is newly synthesized and copied. Patients with hMSH2 mutation tend to develop extracolonic cancers, in particular endometrial cancer, as compared with hMLH1 mutation carriers
  58. 58. To facilitate the clinical diagnosis of HNPCC, the International Collaborative Group on HNPCC (ICG-HNPCC) proposed the Amsterdam Criteria in 1990.
  59. 59. Further liberalization for identifying patients with HNPCC occurred with the introduction of the Bethesda criteria
  60. 60. Revised Bethesda Guidelines (2002) for Testing Colorectal Tumours for MSI Criterion Comment Colorectal cancer diagnosed in a patient less than 50 years of age Presence of synchronous, metachronous colorectal cancer, or other HNPCC-associated tumor, regardless of age Stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain, sebaceous gland adenomas and keratoacanthomas, and small bowel Colorectal cancer with MSI-high histology diagnosed in a patient less than 60 years of age Tumor infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern Colorectal cancer diagnosed in at least on first- degree relative with an HNPCC-related tumor diagnosed under age 50 Colorectal cancer diagnosed in two or more first or second-degree relatives with HNPCC-related tumors, regardless of age.
  61. 61. The mainstay of the diagnosis of HNPCC is a detailed family history. 20% of newly discovered cases of HNPCC are caused by spontaneous germline mutations, so a family history may not accurately reflect the genetic nature of the syndrome. Colorectal cancer, or an HNPCC-related cancer, arising in a person younger than 50 years should raise the suspicion of this syndrome.
  62. 62. Surveillance Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Colorectal cancer 80% Colonoscopy, every 2 yr beginning age 20 yr, annually after age 40 yr or 10 years younger than earliest case in family Endometrial cancer 40%-60% Pelvic exam, transvaginal ultrasound, endometrial aspirate every 1-2 yr, beginning age 25- 35 yr Upper urinary tract cancer 4%-10% Ultrasound and urinalysis every 1-2 yr; start at age 30-35 yr Gallbladder and biliary cancer 2%-18% No recommendation Central nervous system cancer <5% No recommendation Small bowel cancer <5% No recommendation
  63. 63. MANAGEMENT  When colon cancer is detected in a patient with HNPCC, an abdominal colectomy and ileorectal anastomosis is the procedure of choice.  If the patient is a woman with no further plans for childbearing, prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy are recommended.  The rectum remains at risk for development of cancer, and annual proctoscopic examinations are mandatory after abdominal colectomy.
  64. 64. Other forms of cancer associated with HNPCC are treated according to the same criteria as in nonhereditary cases. The role of prophylactic colectomy for patients with HNPCC has been considered in some instances, but this concept has not received universal acceptance. It is an interesting but well-documented fact that the prognosis is better for cancer patients with HNPCC than for non-HNPCC patients with cancer of the same stage.
  65. 65. 3.Peutz-Jeghers syndrome. Autosomal dominant syndrome The combination of hamartomatous polyps of the intestinal tract Germline defects in the tumor suppressor serine/threonine kinase 11 (STK11) gene are implicated in this rare disease.
  66. 66.  Symptoms include: • GI bleeding • Intussusception • Rectal prolapse • Nasal polyposis (chronic sinusitis) Pigmented macules on the lips and digits • Gynecomastia  The most common location of Peutz-Jeghers polyps is in the uppergastrointestinal tract, specifically the upper jejunum.
  67. 67. There is also an increased risk for extraintestinal malignancies including cancer of the breast, ovary ,Cervix, fallopian tubes Thyroid Lung Gallbladder bile ducts pancreas testicles.
  68. 68. PJS Diagnostic Criteria (WHO, 2010) 1.3 or more histologically confirmed PJ polyps, or 2. Any number of PJ polyps with a family history of PJS, 3.Characteristic prominent mucocutaneous pigmentation with a family history of PJS, or 4.Any number of PJ polyps and characteristic prominent mucocutaneous pigmentation.
  69. 69. Duodenal Peutz-Jeghers polyp
  70. 70. Peutz-Jeghers Syndrome surveillance Upper GI endoscopy 2 yearly. Small bowel radiography 2 yearly. Colonoscopy every 2 yr. Ultrasound. Haemoglobin levels annually. Gynaecologic examination, cervical smear, and pelvic ultrasound annually.
  71. 71. Clinical breast exam and mammography at age 25 yr. Clinical testicular exam and testicular ultrasound in males with feminizing features. Nasal endoscopy :to exclude the presence of nasal polyps. Potassium titanyl phosphate (KTP) laser has been used to treat mucocutaneous melanosis of the lips and hands in a patient with PJS
  72. 72. 4.Juvenile polyposis syndrome (JPS) Most common hamartomatous syndrome Inherited as an autosomal dominant trait. A germ-line mutation in the SMAD-4 gene (18q21) accounts for approximately 50% of the reported cases of the syndrome. The term "juvenile" refers to the type of polyp, not the age of onset of polyps.
  73. 73. Characterized by predisposition for hamartomatous polyps in the (GI) tract, specifically in the stomach, small intestine, colon, and rectum. The average age of onset is approximately18 years. Associated with congenital birth defects (15%- 20%) of patients including malrotation, hydrocephalus, cardiac lesions, Meckel's diverticulum, and mesenteric lymphangioma
  74. 74.  Although the diagnostic criteria for juvenile polyposis syndrome aresomewhat controversial, the most commonly used criteria include i. 3 or more juvenile polyps of the colon, ii. polyposis involvingthe entire gastrointestinal tract, iii.or any number of polyps in a member of a family with a known history of juvenile polyps. JUVENILE POLYP
  75. 75. In infancy, patients may present with acute or chronic gastrointestinal bleeding, intussusception, rectal prolapse, or a protein- losing enteropathy.  In adulthood, patients commonly present with either acute or chronic gastrointestinal blood loss.  Polyps are located most frequently in the recto sigmoid region.
  76. 76. Some individuals may only have four or five polyps over their lifetimes, whereas others in the same family may have over a hundred. Most juvenile polyps are benign; however, malignant transformation can occur. Estimates of developing GI cancers in families with JPS range from 9-50%.
  77. 77. Juvenile Polyposis screening Screening by age 12 yr if symptoms have not yet arisen Colonoscopy with multiple random biopsies every several years
  78. 78. 5.Cowden syndrome  Also known as multiple hamartoma- neoplasia syndrome. It is an autosomal dominant condition Complete penetrance by the age 20. Germ-line mutations in the PTEN tumor suppressor gene located at 10q22.  Polyps arise more commonly from
  79. 79. 80% of patients present with benigntumor of the hair shaft. CNS is the second mostinvolved system, with approx 40% having macrocephaly. The majority of patients with Cowden's disease suffer from benign thyroid or breast disease- projected lifetime risk of 10% for thyroid cancer and of 30–50% for breast cancer.
  80. 80. Annual physical exam with special attention to thyroid Mammography at age 30 or 5 yr before earliest breast cancer case in the family
  81. 81. 6.Hyperplastic polyposis syndrome Hyperplastic polyps are found commonly in the large bowel, predominantly in the rectum and sigmoid. Because of their small size, hyperplastic polyps rarely cause symptoms. However, large or multiple hyperplastic polyps occasionally can be responsible for gastrointestinal symptoms.
  82. 82. HPS is a rare condition Characterized by numerous hyperplastic polyps throughout the large bowel that give the mucosa a "studded" look. The endoscopic and radiologic appearance of the mucosal abnormalities closely resembles FAP, but hyperplastic polyposis is not heritable and does not have any extraintestinal manifestations.
  83. 83. 7.Cronkite-Canada syndrome  Characterized by diffuse hamartomatous polyposis  The polyps are Ectodermal abnormalities such as alopecia, onychodystrophy, and skin hyperpigmentation. The syndrome can be distinguished by the diffuse distribution of polyps throughout the entire gastrointestinal tract with exception of the esophagus, which is spared.
  84. 84.  Symptoms include diarrhea, weight loss, nausea, vomiting, and anorexia, as well asparesthesias, seizures, and tetany related to electrolyte abnormalities.  Cancer occurs in the stomach, colon, and rectum, but it remains controversial whether polyps in Cronkite- Canada syndrome possess malignant potential.  As many as 15% of patients with Cronkite-Canada syndrome have a malignant tumor at the time of diagnosis
  85. 85. Five-year mortality rates as high as 55 percent have been reported with most deaths due to gastrointestinal bleeding, sepsis, and congestive heart failure. Treatment has included nutritional support, corticosteroids, acid suppression, and antibiotics
  86. 86. 8.Bannayan-Riley-Ruvalcaba Syndrome  Rare autosomal dominant condition  Includes two other syndromes, both of which, like Cowden's disease, are associated withgenetic alterations in the PTEN gene on chromosome 10q23 , may be considered a variant of juvenile polyposis coli.  No increased risk of colorectal carcinoma, other gastrointestinal malignancies, or extraintestinal malignancy has been documented in these patients.
  87. 87. It is characterized by  hamartomatouspolyps of the gastrointestinal tract  macrocephaly  mental retardation, delayed psychomotor development lipid storage myopathy, Hashimoto's thyroiditis, hyperpigmentationof the skin of the penis.
  88. 88. Research testing of PTEN gene available  No known published recommendations for screening
  89. 89. Gorlin syndrome (GS),  Also termed nevoid basal cell carcinoma syndrome  commonly presents with  Hamartomatous gastric polyps,  Palmar pits, Short metacarpals,  Odontogenic keratocysts,
  90. 90.  Intracranial calcifications,  Skeletal malformations,  Neoplasia (basal cellcarcinoma, ovarian carcinoma, medulloblastoma). (GS) may present in infancy with congenital hydrocephalus, cleft lip and palate, lung cysts, rib and vertebral anomalies, and palmar pits.
  91. 91. Children with GS may present with symptoms of medulloblastoma when younger than 5 years. Dental anomalies and basal cell carcinoma can appear in adolescents.
  92. 92. • Patients with GS may require surgical management for the following: • Craniofacial lesions (cleft lip and palate, jaw cysts, other mandibular lesions) • Abdominal masses (mesenteric cysts, lymphatic cysts, ovarian fibromas) • Diagnostic and therapeutic interventions for potential neoplasia within the CNS (medulloblastoma), skin (basal cell carcinoma), jaw (fibrosarcoma), ovaries (fibrosarcoma), and endometrium (adenocarcinoma) •
  93. 93. PATHOLOGY: WHO Classification • I. Epithelial – Benign – Malignant • Adeno ca >95% • Mucinous adenoca 17% • Signet ring cell ca 2-4% • SCC • Adenosquamous • Undiff/ Unclassified • II. Neuroendocrinal – carcinoid • III. Nonepithelial – Leiomyoma/ lipoma/hemangioma – Leiomyosarcoma • IV. Hematopoietic/ lymphoid(DLBCL) • V. Unclassified • VI. Secondaries • VII. Tumor like lesions • VIII. Epithelial atypia in Ulcerative colitis
  94. 94. Prevention • Guidelines proposed by American College of Gastroenterology (ACG): • A diet that is low in fat and high in fruits, vegetables, and fiber. There may be advantages with cruciferous vegetables and unprocessed forms of cereal fiber. • Maintenance of normal body weight through regular exercise and caloric restriction. • Avoidance of smoking and excessive alcohol use, especially beer. • Dietary supplementation with 3 g of Calcium Carbonate.
  95. 95. SPREAD Local Multidirectional growth progression Intramural- bowel wall penetration Invasion into adjacent organs/ structures Perineural invasion ~10 cm from primary lesion •Lymphomatous • Tumor grade • LVI –Normal lymphatic flow along major arteries to three echelons of LN • Pericolic/ Intermediate /Principal LN
  96. 96. • Hematogenous – Liver- primary site – 40% – Lung- 2nd m/c site – 10-15% have e/o distant metastasis at diagnosis • Peritoneal seeding/ implantation – Intraluminal/ serosal sheding/ by surgical manipulation
  97. 97. CLINICAL PRESENTATION • Related to tumor size/ type/ location • Ascending colon- large, exophytic/ bulky – Pain abdomen – Bleed PR – Unexplained anemia/ fatigability or weight loss • Descending colon- infiltrating/annular/obstructive – Altered bowel habits – Decreased stool calibre – Frequent gas pains, bloating, fullness ,cramps – Mass P/A
  98. 98. DIAGNOSIS• Complete history • Physical examination /DRE • Routine investigations • Confirmatory- Biopsy • Staging workup – CXR – Barium enema – Colonoscopy – USG – CECT abdomen- pelvis – Virtual colonoscopy – MRI – PET • Gold standard- Colonoscopy+ Biopsy •Others •FOBT •Stool cytology •CEA •IHC markers- keratin •Molecular markers- oncogenes •DNA flow cytometry •Immunoscintigraphy •Screening investigations
  99. 99. BARIUM ENEMA – Complementary for colonoscopy – Full column Ba enema misses 1/5th -1/4th of all colon ca and 2/5th of all polypoidal lesions – DOUBLE CONTRAST Ba enema detects almost all colonic lesions~5mm – C/I- Acute /severe IBD, suspected perforation, recent bowel surgery
  100. 100. FLEXIBLE SIGMOIDOSCOPY • Can examine about half of the colon • Less incidence perforations – 1-2/1000 Colonoscopy – 1/10,000 Sigmoidoscopy • Misses proximal lesions, usually used in conjunction with FOBT or BE • Sensitivity-90% /Specificity- 99% (For areas examined by scope)
  101. 101. COLONOSCOPY • Essential procedure for the proper diagnosis/ t/t / and surveillance of patients with nonfamilial colorectal polyps/ patients treated with curative intent • Detect the lesions and biopsy ± removal • Rule out synchronous lesions/ anastomotic recurrence - aggressive colonoscopy indicated in patients with a proven diagnosis • Asymptomatic patients with well documented FOBT and symptomatic patients should have a colonoscopy of entire colon even with normal sigmoidoscopic findings and normal or equivocal Ba enema • Limitations- failure to reach / examine fully – Splenic flexure (10%) – Hepatic flexure (15%) – Caecum (20%)
  102. 102. • VIRTUAL COLONOSCOPY :Thin section helical CT using air contrast and glucagon for bowel sedation and has same efficacy to standard colonoscopy in detecting lesions≥ 6mm. • USG: minimal role of TAUSG – Useful when augmented with retrograde instillation of water into colon k/a HYDROCOLONIC SONOGRAPHY which permits detailed evaluation of bowel wall permitting more precise preop staging
  103. 103. CECT ABDOMEN/ PELVIS • More accurate for T4 than T2/3lesions • Asses extraluminal extent of locally advanced dis. • Limitation: can't detect – Tumor infiltration of pericolic fat – Focal tumor spread external to muscularis propria – Pericolonic LN <1 cm – Liver mets <1cm • Overall accuracy staging primary – 70% • Sensitivity LN detection- 45%
  104. 104. • FDG-PET – To asses response to RT/CCT – Detect occult areas of recurrent CRC patients considered for re exploration • MRI- not superior to CT • TUMOR MARKER : CEA – No role in diagnosis/ screening of ca colon – Correlate with tumor burden and prognosis – Monitoring tool for patients treated with curative intent – Post op CEA level is more sensitive indicator of recurrence – Normal :
  105. 105. AJCC/ UICC STAGING
  106. 106. TREATMENT • SURGERY- Primary • RADIOTHERPY- Adjuvant • CHEMOTHERAPY-Adjuvant and metastatic • TARGETED / IMMUNOTHERAPY- Adjuvant and metastatic
  107. 107. SURGERY • SURGRY is the GOLD STANDARD and principle therapy of primary and non metastatic ca colon – Curative – Palliative – Accurate disease staging – Guides adjuvant treatment • Likelihood of cure is greater when disease is detected at early stage
  108. 108. SURGERY • PRINCIPLE: Standard treatment •WIDE RESECTION of the involved segment including the lymphatic drainage areas+ mesocolon+enblock resection of the neighbouring involved organs •AIM •To excise the primary lesion with adequate margin ~5 cm of normal bowel proximal and distal to the tumor •To reconstitute bowel continuity •To avoid complications •To inspect the other viscera for mets
  109. 109. • TYPES OF SURGICAL RESECTION – Right Hemicolectomy – Extended Right Hemicolectomy – Left Hemicolectomy – Segmental resection – Total Abdominal Colectomy: UC, FAP Syndrome/ FH • Sx approach determind by the lesion size and location • Location determines what region of bowel is removed, and the extent of its resection is dictated by its vascular and lymphatic supply • Minimum of 12-15 LNs should be removed
  110. 110. Right Colectomy. A right colectomy is used to remove lesions or disease in the right colon and is oncologically the most appropriate operation for curative intent resection of proximal colon carcinoma. The ileocolic vessels, right colic vessels, and right branches of the middle colic vessels are ligated and divided. Approximately 10 cm of terminal ileum are usually included in the resection. A primary ileal-transverse colon anastomosis is almost always possible.
  111. 111. • Extended Right Colectomy. An extended right colectomy • may be used for curative intent resection of lesions located at the • hepatic flexure or proximal transverse colon. A standard right colectomy • is extended to include ligation of the middle colic vessels • at their base. The right colon and proximal transverse colon are resected.
  112. 112. • Transverse Colectomy. Lesions in the mid and distal transverse • colon may be resected by ligating the middle colic vessels and resecting the transverse colon, followed by a colocolonic • anastomosis.
  113. 113. • Left Colectomy. For lesions or disease states confined to the distal transverse colon, splenic flexure, or descending colon, a left colectomy is performed. • The left branches of the middle colic vessels, the left colic vessels, and the first branches of the sigmoid vessels are ligated.
  114. 114. • Extended Left Colectomy. An extended left colectomy is an option for removing lesions in the distal transverse colon. • In this operation, the left colectomy is extended proximally to include the right branches of the middle colic vessels.
  115. 115. • Sigmoid Colectomy. Lesions in the sigmoid colon require • ligation and division of the sigmoid branches of the inferior mesenteric artery. In general, the entire sigmoid colon should be resected to the level of the peritoneal reflection and an anastomosis created between the descending colon and upper rectum. • .
  116. 116. • Full mobilization of the splenic flexure is often required to create a tension-free anastomosis.
  117. 117. • Total and Subtotal Colectomy. Total or subtotal colectomy is occasionally required for patients with fulminant colitis, attenuatedFAP, or synchronous colon carcinomas. • In this procedure, the ileocolic vessels, right colic vessels, middle colic vessels,and left colic vessels are ligated and divided.
  118. 118. • The superior rectal vessels are preserved. If it is desired to preserve the sigmoid, the distal sigmoid vessels are left intact, and an anastomosis is created between the ileum and distal sigmoid colon (subtotal • colectomy with ileosigmoid anastomosis). • .
  119. 119. • If the sigmoid is to be resected, the sigmoidal vessels are ligated and divided, and • the ileum is anastomosed to the upper rectum (total abdominal colectomy with ileorectal anastomosis). • If an anastomosis is contraindicated, an end ileostomy is created, and the remaining sigmoid or rectum is managed either as a mucus fistula or a Hartmann’s pouch
  120. 120. • Total Proctocolectomy. In this procedure, the entire colon, rectum, and anus are removed and the ileum is brought to the skin as a Brooke ileostomy
  121. 121. ADJUVANT THERAPY BASIS • Despite curative surgery half of these patients suffer INCURABLE TUMOR RECURRENCE leading to cancer related death • Therefore there is a need of adjuvant therapy to improve DFS and OS • Establishment of adjuvant therapy as a standard treatment in stage III colon cancer based on improvement in overall survival • In stage II colon cancer adjuvant treatment remains controversial
  122. 122. Adjuvant Therapy for Colon Ca • Stage I Colon: Surgery alone • Stage II Colon: Adjuvant chemotherapy use is controversial. Indicated beyond stage IIA. Considered for the following: – Obstructed or perforated colon cancer – High-risk histology-LVI +/ extramural spread or PD histo. – Involvement of adjacent organs (T4 lesion) – Inadequate LN sampling (<13 LNs retrieved) – Elevated preop CEA – High S-phase fraction – Tumor not having high level of MSI – 18q deletion
  123. 123. RADIATION• Rationale of adjuvant radiation – Based on patterns of failure following potential curative surgery – Primary determinant of failure patterns in CRC is the location of tumors in reference to peritoneal reflection – T/t recommendation are based on the stage of disease and tumor location in reference to peritoneal reflection. If tumor is completely above the peritoneal reflection, its treated as colon ca and if its below, then treated as rectal ca • RT is an effective but a local modality • Adjuvant RT role less well defined due to difference in natural history of Ca colon
  124. 124. • All stages combined m/c failure site in ca colon is abdominal (liver) rather than local • When local failure, its extrapelvic and symptoms are less debilitating as seen in ca rectum • Overall incidence of local failure relatively low, depends on stage and as high as 35% in stage III & IV • Higher risk- Partially retroperitonealized regions • Adjuvant RT use limited to – Clinical presentations with the risk of local failure is sufficiently high enough (10%) – When an adequate dose can be delivered to the site at the highest risk of failure
  125. 125. Failure pattern following curative surgery Series Stage n LF (%) Abdominal failure (%) Distant failure(%) Gunderson et al All T3-4 and /or N1-2 91 72 22 17 4 6 7 7 Willet et al All T3-4 and /or N1-2 533 395 6 8 11 14 4 Minsky et al All T3-4 and /or N1-2 284 229 6 4 8 10 3 5
  126. 126. • Indications of RT – Incomplete excision/ Residual disease – Positive resection margins – B2, B3, C2 tumors arising in the immobolized bowel with close CRM(<1 cm) – Fixed tumors i.e. caecal and sigmoidal ca – Tumor a/w perforation/ obstruction/fistula/abscess
  127. 127. Technique• Bowel preparation • Positioning – NON SIGMOID CA- Lat. Decubitus position by two parallel opposed fields – SIGMOID CA- Prone position by 3-4 fields to exclude small bowel and maximize homogeneity in treatment volume • Immobilization • Target volume delineation • Simulation- Conventional/CT • Portal delineation and check films • Marking on the body
  128. 128. • TUMOR BED / FIELD • Involved segment of large bowel and, when present, the adjacent organ or structures to which it was adherent or invading • If adherent to partially resected organ→ whole organ has to be treated if within tolerance • If adherent to structure (pelvic side wall, psoas, diaphragm) → 3-5 cm margins beyond area of adherence • Pelvic nodal groups at risk • Tumor bed + immediate adjacent PA or pelvic LNs+ 3 cm margin – Dose- 45- 50 Gy/25#/ 4.5-5 weeks • KIDNEY SHIELDING after 8#
  129. 129. Caecum and proximal ascending colon
  130. 130. Mid ascending colon
  131. 131. Distal descending colon
  132. 132. Middle sigmoid colon adherent to left pelvic sidewall or proximal sigmoid
  133. 133. Distal ascending colon and hepatic flexure
  134. 134. Splenic flexure and proximal descending colon
  135. 135. Middle descending colon
  136. 136. Palliative - Sigmoid colon adherent to the UB
  137. 137. • Critical normal (dose limiting) tissues – Small intestine: max 45 Gy (30 Gy by WART) – Liver : 2/3rd of liver should get <30 Gy – Kidneys: 2/3rd of one kidney should get <20 Gy – Spinal cord: max dose to spinal cord< 50 Gy
  138. 138. HISTORICAL • WART – To treat the volume at risk with a potentially curative dose of radiation required for microscopic disease…… the whole abdomen need to receive 45 Gy – Rationale- High incidence of local failure – Dose- 30 Gy , then cone down to the primary tumor bed – Combined results- In 3 series – 5FU- in field (abdominal) failure rate: 12-50% and 3 yr survival ~50% – SWOG 8572- T3N1-2M0→ WART+ CVI 5FU f/b a monthly cycle of CVI 5FU. WART 30 Gy f/b boost of 1.6 Gy for 10# • Median FU 5yr: DFS-58%, OS- 67%, Toxicity-17%
  139. 139. NEWER RT Techniques – IOERT- Radiation boosting for dose intensification –T4 tumors with uncertain margins/ invading adjacent structures –Preop EBRT + 5-FU based CCT followed by resection with or without IOERT and postop systemic therapy • Advantage – Visual contrast of target volume – Homogenous treatment of controlled thickness of tissue with tumor – Protection of mobile uninvolved normal tissue • Disadvantage – Increase incidence of late normal tissue complications • Dose- With 9-15 Mev electron, 10-20 Gy normalized at 90%
  140. 140. CHEMOTHERAPY • Adjuvant: Aim is to destroy microscopic metastatic disease and preventing death from metastasis as substantially no. of patients treated surgically with curative intent eventually died of metastatic disease • Metastatic setting/Palliative
  141. 141. Historical data in favor of chemotherapyHistorical data in favor of chemotherapy FU, semustine & VCR (MOF) NSABP-C-01 randomized N(-), N(+) patients BCG Sx alone MOF – 5 yrs DFS 58%, OS – 67% DFS( %) OS(%) Stage II Sx alone 71 72 Sx→ 5FU+Levamisole 79 72 Stage III Sx alone 44 Sx→ 5FU+Levamisole 61 Death rate ↓ 33% Rec. rate ↓40% Sx→ Levamisole NS NCI 1990 consensus established adjuvant CCT as standard of care of patients with node (+) resected ca colon
  142. 142. 5FU 370-400mg/m2 + LCV 200mg/m2 D1-D5x4 weeklyx6 cycles NCCTG/ NCI 3 yr survival (%) RFS(%) Gr 3 toxicity 5FU+LCV(Mayo)x 6 months 83.2 68.6 High PVI 5FU 200mg/m2 /d x 12 weeks 87.9 80 Less
  143. 143. • QUASAR (Quick and Simple and Reliable) – No difference in survival b/w HDLCV and LDLCV – Worse survival with levamisole – No difference in outcomes for dailyx5 and weekly schedules – Once weekly regimen less toxic INT-0089 Treatment duration (weeks) 5 yr DFS(%) 5 yr OS(%) 5-FU +levamisole 52 56 63 5-FU + weekly HDLCV (Roswell park ) 32 59 65 5-FU +LDLCV on d1- 5 (Mayo clinic) 24 60 66 Mayo Clinic schedule of 5- FU/LCV + levamisole. 24 60 67
  144. 144. • LV5FU2 vs Mayo clinic regimen – LCV 2 hr infusion f/b 5FU bolus and then a 22 hr CVI of 5FU d1-2 x biweekly – Superior response rate and PFS of LV5FU2 – DFS and OS similar yet toxicities are less with LV5FU2 • Oral fluoropyrimidines- Capecitabine and UFT – In metastatic disease efficacy comparable with Mayo schedule
  145. 145. MOSAIC Trial: LV5FU2 vs LV5FU2 + FOLFOX-4 LV5FU2 (n = 1,123) (%) FOLFOX-4 (n = 1,123) (%) 3 yr DFS stage III 66 72 3 yr DFS stage II 84 87 OS NA NA Grade 3-4 neutropenia 5 41 Neutropenic fever 0 1 Grade 3-4 diarrhea 0 1 Grade 3-4 vomiting 7 11 Neuropathy, any grade 0 92 Neuropathy, grade 3 0 12 Persistent neuropathy, grade 2-3, 1 year after t/t 0 5
  146. 146. Commonly Used Fluorouracil (5-FU) Regimens Regimen Reference Schedule Mayo clinic Poon et al., 1989 LV 20 mg/m2 , followed by bolus 5FU, 425 mg/m2 each daily d1-d5 repeated 4 weekly for 1st 2 cycles, than q35d thereafter Roswell Park Haller et al., 1998 LV 500 mg/m2 over 2 h; 5-FU 500 mg/m2 bolus 1 h into LV infusion. weekly x 6 wks, every 8 wks Low-dose weekly LV., Jager et al., 1996 LV 20 mg/m2 over 5-15 min, followed by bolus 5- FU 500 mg/m2 ; weekly x 6 wks, every 8 weeks Protracted venous infusion Lokich et al., 1989 5-FU 300 mg/m2 /day by continuous infusion AIO (weekly 24-h infusion) Kohne et al., 1998 LV 500 mg/m2 over 2 h, followed by 5-FU 2,600 mg/m2 over 24 h, weekly LV5FU2 de Gramont et al., 1997 LV 200 mg/m2 over 2 h days 1, 2, followed by bolus 5-FU 400 mg/m2 /day 1 and 2, f/b 5-FU 600 mg/m2 over 22 h, day 1 and 2: every 14 days Simplified LV5FU2 Adapted from Andre et al., 1999 LV 400 mg/m2 over 2 h, followed by bolus 5-FU 400 mg/m2 , followed by 5-FU 2,400-3,000 mg/m2 over 46-48 h; cycles repeated every 14 days
  147. 147. Commonly Used Irinotecan/5-FU Combination Regimens Regimen Study Schedule IFL Saltz et al; 2000 Irinotecan 125 over 90 min, followed by LV 20 mg/m2 by brief infusion, followed by bolus 5-FU 500 mg/m2 ; weekly for 4 weeks , repeated every 6 weeks FOLFIRI Douillard et al., 2000 Irinotecan 180 mg/m2 over 2 h; LV 200 mg/m2 concurrently with irinotecan (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m2 , followed by 5- FU 600 mg/m2 infusion over 22 h. Irinotecan given day 1 only. All other meds given days 1 and 2. Cycle repeated every 14 days FOLFIRI (simplified) Andre et al., 1999 Irinotecan 180 mg/m2 over 2 h; LV 400 mg/m2 concurrently with irinotecan (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m2 , followed by 5- FU 2,400-3,000 mg/m2 infusion over 46-48 h. Cycle repeated every 14 days FUFIRI Douillard et al., 2000 Irinotecan 80 mg/m2 , then LV 500 mg/m2 , followed by 5-FU 2,300 mg/m2 ; all drugs given weekly for 6 weeks, repeated every 7 weeks
  148. 148. Selected Commonly Used Oxaliplatin/5-FU Combination Regimens Regimen Study Schedule FOLFOX-4 de Gramont et al., 2000 Oxaliplatin 85 mg/m2 over 2 h; LV 200 mg/m2 concurrently with oxaliplatin (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m2 , followed by 5- FU 600 mg/m2 infusion over 22 h. Oxaliplatin given day 1 only. All other meds given days 1 and 2. Cycle repeated every 14 days FOLFOX-6 Tournigand et al., 2004 Oxaliplatin 100 mg/m2 over 2 h; LV 400 mg/m2 concurrently with oxaliplatin (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m2 , followed by 5- FU 2,400-3,000 mg/m2 infusion over 46-48 h. Cycle repeated every 14 days Modified FOLFOX-6 (mFOLFOX- 6) Widely used in current phase III trials, but not published Oxaliplatin 85 mg/m2 over 2 h; LV 400 mg/m2 concurrently with oxaliplatin (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m2 , followed by 5- FU 2,400-3,000 mg/m2 infusion over 46-48 h. Cycle repeated every 14 days FUFOX Grothey et al., 2002 Oxaliplatin 50 mg/m2 over 2 h, followed by LV 500 mg/m2 , followed by 5-FU 2,000 mg/m2 over 24 h, weekly for 5 weeks, repeated every 6 weeks.
  149. 149. Single Agents: 5FU/Leucovorin (Mayo, Roswell, DeGramont) Capecitabine Oxaliplatin Irinotecan Combinations: Oxaliplatin + 5FU (FOLFOX) Irinotecan/5FU/Leuco (IFL, Saltz) Irinotecan + 5FU (FOLFIRI) Capecitabine + Oxaliplatin (Capox) Capecitabine + Irinotecan (Capiri) Chemotherapy in CRC
  150. 150. 5-Fluorouracil + Leucovorin (Mayo Clinic Schedule) NCCTG 5-FU: 425 mg/m2 IV on d1 – 5 LCV : 20 mg/m2 IV on d1 – 5 before 5 - FU Repeat cycle every 4 – 5 weeks for a total of 6 cycles Oxaliplatin + 5-Fluorouracil + Leucovorin (FOLFOX4) Oxaliplatin: 85 mg/m2 IV on day 1 5-Fluorouracil 400 mg/m2 IV bolus, followed by 600 mg/m2 IV continuous infusion for 22 hours on days 1 and 2 Leucovorin: 200 mg/m2 IV on days 1 and 2 as a 2-hour infusion before 5-Fluorouracil Repeat cycle every 2 weeks Chemotherapy as adjuvant in CRC
  151. 151. Stage IV/ Metastatic Ca Colon • Selectively resectable group – Options: Regional strategies • Organ-specific infusional therapy • Isolated or continuous perfusion therapy • Radiofrequency ablation • Cryotherapy • Surgical debulking • Radiation – Surgical metastsectomy
  152. 152. • Unresectable disease- generally incurable – Goal: Palliation- symptom control/ control of tumor growth/ lengthen PFS and OS – Palliative chemotherapy: indication if following guidelines are met • Favorable performance status • Acceptable BM / renal / hepatic function • Reasonable nutritional status • Well motivated patients
  153. 153. Oxaliplatin + 5-Fluorouracil + Leucovorin (mFOLFOX7) Oxaliplatin: 100 mg/m2 IV on day 1 5-Fluorouracil: 3000 mg/m2 IV continuous infusion on days 1 and 2 for 46 hours Leucovorin: 400 mg/m2 IV on day 1 as a 2-hour infusion before 5- fluorouracil Repeat cycle every 2 weeks Irinotecan + 5-Fluorouracil + Leucovorin (FOLFIRI Regimen) Irinotecan: 180 mg/m2 IV on day 1 5-Fluorouracil: 400 mg/m2 IV bolus on day 1, followed by 2400 mg/m2 IV continuous infusion for 46 hours Leucovorin: 200 mg/m2 IV on day 1 as a 2-hour infusion prior to 5- fluorouracil on days 1 – 5 administered before 5 - Fluorouracil Repeat cycle every 2 weeks Capecitabine Capecitabine: 1250 mg/m2 PO bid on days 1 – 14 Repeat cycle every 21 days for a total of 8 cycles. Dose may be decreased to 850- 1000 mg/m2 PO bid on days 1-14 to reduce the risk of toxicity without Chemotherapy as adjuvant in CRC
  154. 154. Capecitabine + Oxaliplatin (XELOX) Capecitabine: 1000 mg/m2 PO bid on days 1 - 14 Oxaliplatin: 130 mg/m2 IV on day 1 Repeat cycle every 21 days. May decrease dose of capecitabine to 850 mg/m2 PO bid and dose of oxalioplatin to 100 mg/m2 IV to reduce the risk of toxicity without compromising clinical efficacy Capecitabine + Irinotecan (XELIRI) Capecitabine: 1000 mg/m2 PO bid on days 1 - 14 Irinotecan: 250 mg/m2 IV on day 1 Repeat cycle every 21 days. May decrease dose of capecitabine to 850 mg/m2 PO bid and dose of irinotecan to 200 mg/m2 IV to reduce the risk of toxicity without compromising clinical efficacy Chemotherapy as adjuvant in CRC
  155. 155. • Stage II: IMPACT metaanalysis – Sx alone-81% / Adj. 5FU+ LCV – 83% – Long term OS statistically insignificant – Satge II patients with poor prognostic factors should be considered for adjuvant chemotherapy • Stage III: – In the absence of medical or psychiatric C/I, patients with node(+) colon ca should receive postop chemotherapy – Daily X 5d Mayo schedule – more toxic, shouldn’t be used – At the very least, a 5-FU based regimen be appropriate, and ~a half year of therapy supported by the majority of trials – Oral capecitabine or UFT/LCV acceptable alternatives if a fluoropyrimidine-only approach is selected – FOLFOX schedule is now the most widely used adjuvant t/t – Modified FOLFOX -6 –NCI intergroup adjuvant trials, is routinely used because of its greater convenience – FOLFIRI shouldn’t be used in the adjuvant setting due to increased risk of early death and no long-term benefit
  156. 156. Investigational adjuvant approaches • Portal vein infusion (↑DFS by 10%) • Intraperitoneal chemotherapy- stage III- 43% ↓mortality • Edrecolomab- not used • Vaccine- Canarypox virus encoded gene induce CEA specific T-cell response in patients with advanced adenoca • ASI
  157. 157. Targeted therapy in advanced colon cancerTargeted therapy in advanced colon cancer  40% patients undergoing systemic CT for advanced disease do not achieve tumor shrinkage  Molecular warfare focusing on dissection of molecular pathways resulting in tumor growth and progression
  158. 158. Targeting the angiogenesis process  Tumor growth and metastasis is strongly linked with angiogenesis process. The vascular network in the tumor growth involves different complex pathways. VEGF is the most potent and specific angiogenic factor and its expression in CRC is correlated with recurrence and prognosis. Two different strategies devised to target VEGF are: 1) Developing MCA directed against VEGF 2) Developing intervention to VEGF pathway involving small different molecules with tyrosine kinase inhibition activity directed towards the VEGF receptors
  159. 159. Bevacizumab Anti – VEGF monoclonal antibody
  160. 160. Bevacizumab  Approved for use in metastic colo rectal carcinoma in cimbination with IV 5FU as first- line  Dose: 5 mg/kg IV over 90 mins every 2 weeks • Avastin 100 mg (4 ml) & 400 mg (16 mg) • Toxicities: GI perforation, wound dehiscence, hemorrhage, risk of arteriel TE events (MI, stoke), hypertension, infusion-related toxicity, proteinuria and nehprotic syndrome
  161. 161. The importance of EGFR in metastatic colorectal cancer  EGFR is involved in the progression of mCRC  Patients with EGFR-expressing tumors have a shorter survival  EGFR is expressed in 75 – 89% of mCRC
  162. 162. Cetuximab (C225)  Chimeric MCA to EGFR  Binds with high affinity to transmembrane domain of EGFR and blocks binding of natural ligands (EGF, TGF)  Inhibits EGFR function and downstream signal transduction pathways, promoting apoptosis  Synergistic inhibition with chemotherapy and radiation .
  163. 163. Cetuximab  Approved for use in EGFR expressing metastatic CRC in combination with irinotecam in patients refractory to irinotecam or as mono therapy in pts intolerant to irinotecam  Dose: Loading dose of 400 mg/s.m., then 250 mg.s.m. IV weekly  Erbitux: 50 ml vials, 2 mg/ml  Infusion-related toxicity (40-50%), rash, ILD, asthenia & fatigue, paronychia
  164. 164. Cetuximab in EGFR expressing metastatic CRC: first line trials Hoehler T. et al. Proc ESMO 2004 Van Cutsem E. et al. Proc ESMO 2004 Reference 21% resection of livermetastases remarks 21 %2%PD 24 %17%SD 55 %81% (74% conf.) (61-88) CR + PR (95% CI) 3843Total patients FUFOX + cetuximab FOLFOX + cetuximab
  165. 165. FOLFIRI 5-FU bolus 400 mg/m2 , infusion 2400 mg/m2 + Irinotecan 180 mg/m2 + Leucovorin 400 mg/m2 every 2 wks (n = 609) Patients with previously untreated EGFR- expressing metastatic colorectal cancer, stratified by geographical region, ECOG PS (N = 1217) FOLFIRI + Cetuximab 5-FU bolus 400 mg/m2 , infusion 2400 mg/m2 + Irinotecan 180 mg/m2 + Leucovorin 400 mg/m2 every 2 wks Cetuximab 400 mg/m2 initial dose, then 250 mg/m2 wkly (n = 608) Van Cutsem E, et al. ASCO 2007. Abstract 4000. CRYSTAL Trial FOLFIRI ± CetuximabCRYSTAL Trial FOLFIRI ± Cetuximab
  166. 166. PROGNOSITC FACTORS • ADVERSE C/F – Younger age < 40 yr – Long symptomatology – Obstruction/ perforation – Ulcerative lesion – BT • ADVERSE PATHOLOGY – High grade – Colloid/ Signet ring cell – LVI – Perineural invasion – Aneuploidy – ↑↑ CEA/ collagen – Cell surface antigens CA-19.9 – Local immune response •Most important guide to prognosis is STAGE of the disease i.e. depth of penetration and number of LNs involved
  167. 167. Rational post therapy surveillance programme • CEA every 3 month x 1st 3 yrs, than 6 monthly up to 5 yrs (CEA detects 80% recurrence) and • Complete physical examination on each FU • CECT abdomen pelvis yearly x 1st 3 yrs • Colonoscopy every 3 to 5 yrs • FDG-PET- rising CEA in two consecutive tests in absence of imageable disease by CT
  168. 168. RISING CEA COLONOSCOPY FDG-PET NORMALNORMAL CXRCXR CECT
  169. 169. ACS colorectal cancer screening guidelinesACS colorectal cancer screening guidelines* Fecal occult blood test (FOBT)† or fecal immunochemical test (FIT) every year, or Flexible sigmoidoscopy every 5 years, or An FOBT† or FIT every year plus flexible sigmoidoscopy every 5 years (of these first three options, the combination of FOBT or FIT every year plus flexible sigmoidoscopy every 5 years is preferable), or Double-contrast barium enema every 5 years, or Colonoscopy every 10 years • * Beginning at age 50, men and women who are at average risk for developing colorectal cancer should have one of the five screening options listed. Those at increased risk for colorectal cancer should undergo screening earlier and at more frequent intervals. • † For FOBT or FIT, the take-home multiple sample method should be used. • Source: “Can colorectal polyps and cancer be found early?” American Cancer Society (www.cancer.org); 2005 Accessed Sept 2008.
  170. 170. THANK YOU
  171. 171. Population Screening • Simple • Cheap • Reliable • Safe • Acceptable CRC fulfills many of these criteriaCRC fulfills many of these criteria for effective screeningfor effective screening

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