GI CANCER: PART 1
| MANAGING THE PRIMARY IN METASTATIC COLORECTAL CANCER—Robert Gryfe, MD, Assistant Professor,
Department of Surgery, University of Toronto Faculty of Medicine, Toronto, ON
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| Evidence: scanty data on incurable colorectal cancer; Surveillance, Epidemiology, and End Results (SEER) Program database
reflects current practices; slight downstaging due to screening; 20% diagnosed with distant metastases; 10-mo median
survival; resection practice—65% of patients with incurable disease (stage IV) have primary resection; colon
cancers resected more often than rectal; younger patients; no sex bias; more nonblack patients; colon- and rectal-resected
patients had longer survival rates than unresected patients; editorial suggestions (A. Cohen)—patients with colon cancer
and no or minimal symptoms and minimal disease should be resected; no surgery if extensive disease present; in rectal
cancer, no symptoms, no surgery; issues with retrospective data—no-resection group includes patients treated
palliatively; fit patients more likely to be resected; colon cancer resected more often than rectal; less extensive cancers
more likely to be resected; these biases lead to improved patient survival in resected-primary group; not all stage IV cancers
same
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| Memorial Sloan-Kettering case series: 5-yr survival rate 20% to 40% in patients undergoing resection with curative
intent for liver or lung metastases; aggressive surgical approach appropriate in medically fit individuals with resectable
liver or lung metastases but without evidence of other unresectable diseases
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| US Department of Veterans Affairs data: 30-day mortality after any colon cancer resection; chance of dying
postoperatively—3 times greater with ascites and twice greater with disseminated cancer; ascites second only to life-threatening
illness or moribund conditions as independent predictor of postoperative survival
|
| Surgical resection of primary in incurable stage IV cancer: no randomized controlled trials; entire literature
found in 11 studies, 1400 patients total; range from 24 to 362 patients, median age 80 yr; 6 studies compared resection
to no resection; 4 studies specifically identified asymptomatic or minimally symptomatic patients (important factor)
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 | Speaker’s analysis of data (not meta-analysis): resected groups—mortality rate 6.6% (higher than standard colon cancer
resection); morbidity rate 22%; 4% of patients with primary resection required other surgery prior to death; 13-mo median
survival in resected group (similar to SEER); patients undergoing palliative surgery (with no resection) had high postoperative
mortality rate (20%); poor median survival (<3 mo); nonsurgical (without bypass or resection) groups—<20%
required surgery prior to death; 10-mo median survival (higher than SEER data)
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| Treatment options: palliative chemotherapy—randomized controlled study compared regimen of 5-fluorouracil (5-
FU), irinotecan, and leucovorin against same agents with bevacizumab (Avastin; antiangiogenesis drug); 20-mo median
survival with bevacizumab; Canadian patients had <16 mo survival; study included patients progressing to stage IV (but
unable to extract specific data); resection commonly used and associated with 12-mo survival; resection more common in
younger patients with colon cancer; >80% of unresected patients do not require surgery prior to death; median survival 10-
mo; 15 to 20 mo survival with modern palliative chemotherapy (not specific to group that presents with metastases); aggressive
medical management may lead to downstaging and curative-intent resection (equivalent in one study of resected
and unresected primary patients); colonic resection in patients with malignant ascites associated with significantly increased
perioperative mortality and poor survival; non-resection palliative surgery associated with high perioperative mortality
and poor survival
|
| GI STROMAL TUMORS: RECOGNITION AND MANAGEMENT—Calvin Law, MD, Assistant Professor, Department
of Surgery, University of Toronto Faculty of Medicine, Toronto, ON
|
| Clinical recognition: one half lesions gastric, one quarter in small intestine, remainder scattered throughout intestinal system;
symptoms vague because tumors not mucosa-based but soft and bleed within themselves; in asymptomatic patient with
tumor found on ultrasonography, perform endoscopy to rule out mucosal lesion; symptomatic lesion may be due to sudden enlargement
from bleeding; soft tumors pushed out of way during endoscopy, so appearance normal; proceed with further imaging
studies; ultrasonography report may say—vascular-looking tumor; cyst; necrosis; abscess; multiloculated appearance;
computed tomography (CT) findings—report may describe arterially enhancing rim, multiloculated appearance, cystic appearance,
possible abscess (do not biopsy percutaneously); triphasic imaging—helps determine origin of tumor; CT helps
to—confirm and characterize mass, evaluate extent of mass, determine metastasis, and assess tumor resectability (consult radiologist
for clinical context)
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| Gastrointestinal stromal (GIST) lesions: “Is it easy, is it nasty, or is it everywhere?”; decision guides therapy; easy
means resectable isolated small bowel tumor, not metastatic; on greater curve of stomach; excise, ensure clear margins, and perform
complete resection; do not break tumor—appears firm and hard, but really soft and fragile; tumor creates adhesions and
parasitizes arterioles from other structures; retract, manipulate, and manage adhesions with great care; avoid tearing; lymph
node involvement—uncommon; lymphadenectomy necessary only if suspicious masses felt; margins—1 to 2 cm; must be
negative on frozen section; preserve organ function while removing tumor; most GISTs submucosal and “pop out”; usually
able to find margin; goal is cure; positive margins or cracked tumor not cure; if tumor worse than anticipated—try extra retraction;
“better not to crack tumor, close and send than to crack tumor, close, and send”; laparoscopy— controversial; no
good evidence that laparoscopy as safe as open surgery, but same principles apply, ie, do not break tumor, get negative margins,
and preserve function; if unable to do this laparoscopically, switch to open surgery
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| After surgery: confer with pathologist; leiomyoma, leiomyosarcoma different from GIST; amount of CD117 protein not important;
all can respond to further therapy and have good prognosis; all GISTs malignant; patient outcome based on frequency
of recurrence; risk high (poor prognosis) if tumor >10 cm or if >10 mitoses per 50 high-power fields; patients do best if tumor
<2 cm and <5 mitoses per 50 high-power fields; even people with small tumors have recurrences and die of GIST; if patient
low risk, consider clinical trial or observation; consider enrolling patient with larger tumor and more mitoses in clinical trials
using adjuvant imatinib; probably beneficial for long-term survival
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| “Nasty” tumors: require total gastrectomy, Whipple procedure, abdominoperineal resection (APR); relatively functional, not
resectable; consider neoadjuvant imatinib; risk of bleeding 5% (use only if shrinking tumor would lead to better outcome);
treatment of aggressive tumors requires multidisciplinary consultations
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| Recurrent tumors: due to breakage, tumor left behind, or local peritoneal recurrence; survival matches metastatic disease;
data unclear; metastatic disease—refer to medical oncologist; good treatment options available; median survival 4.5 yr using
imatinib
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| CONTROVERSIES IN SURGICAL MANAGEMENT OF FAMILIAL POLYPOSIS COLI—Kenneth W. Sharp,
MD, Vanderbilt University School of Medicine, Nashville, TN
|
| Background: incidence 2 per 100,000 population; colorectal cancer has strong familial tendency; familial polyposis purest
form, leads to colorectal cancer; hereditary nonpolyposis colon cancer accounts for 10% to 20% of colon cancers in United
States; colon lined with adenomatous (not hyperplastic) polyps
|
| Categories: familial adenomatous polyposis (FAP)—few extra-intestinal manifestations; Gardner’s syndrome (subset
of FAP)—characteristic extraintestinal manifestation; attenuated familial polyposis (AFAP)—subgroup; >25 and <100
polyps in colon; different mutation in adenomatous polyposis coli (APC) gene; seen in older patients; less malignant potential
than true FAP; Turcot’s syndrome—<1% of FAP cases; colonic polyposis associated with central nervous system tumors
(eg, medulloblastoma); Cronkite-Canada syndrome—rare; true FAP—>100 colonic adenomatous polyps;
autosomal dominant; incidence calculated at 1 in 10,000, but realistic number probably half that; due to mutation of APC
gene; >400 mutations described; location of mutation affects virulence (less virulent at far end of gene); positive family history
in 70% of patients, ie, 30% index mutations; cancer develops 10 to 15 yr earlier than sporadic colorectal cancer; mean
age for development of colon polyps 16 yr, but can be as young as 2 yr of age; 39 yr mean age for development of colon cancer;
without colectomy, 93% have colorectal cancer by 50 yr of age
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| Extracolonic manifestations: in FAP and Gardner’s syndrome; gastric polyps—in ≤90% of patients; majority benign
fundic gland polyps, few adenomatous; lifetime risk for gastric cancer <1%; duodenal polyps—develop in 70% to
90% of patients with FAP; difficult to determine who develops ampullary polyp with duodenal sparing, who develops
duodenal polyp with ampullary sparing, who develops both; duodenal polyps carry significant (≤10%) cancer risk; periampullary
cancer more common than duodenal; second leading cause of death in patients without colon resection, leading
cause of death after resection; small bowel adenomas common, cancer rare; distal ileal polyps—more common than
proximal jejunal or ileal polyps; pouch adenomas—common after ileoanal pouch anastomosis (≈35%); cancer rare
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| Gardner’s syndrome: extracolonic and extraintestinal manifestations—osteomas of skull and jaw; epidermoid
cysts; odontomas; subcutaneous fibromas; congenital hypertrophy of retinal pigment epithelium (CHRPE); occurs before
development of colonic adenomas; tumors—more common in Gardner’s syndrome than in patients with FAP; ≈10% of
FAP, majority on abdominal wall; mesenteric desmoid tumors occur in ≈20% and have 2% to 4% mortality rate in patients
with FAP; following prophylactic colectomy, second leading cause of death (after periampullary malignancy) in
patients with FAP; death due to bowel or ureteral obstruction; rarely seen until after abdominal surgical procedure, eg,
colectomy
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| Malignancies in FAP: colorectal in 100% of patients not treated with prophylactic colectomy; duodenal/periampullary
second most common; increased risk for thyroid (low single digits), brain (in Turcot’s syndrome), gastric (<1%), pancreatic,
bile duct, and liver cancers
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| Management controversies: screening—children of patients with FAP; age variable; in speaker’s experience, can be
as early as 4 yr of age; APC gene test commercially available; ≈800 mutations described, not all tested for (negative APC
analysis does not guarantee absence of FAP); speaker recommends colonoscopy in early teens, repeated every 3 to 5 yr;
colectomy—patients with large bleeding polyps; polyps with dysplastic changes on biopsy; challenging cases are asymptomatic
patients 14 to 16 yr of age with multiple polyps 1 cm, no dysplasia, and no bleeding; speaker believes teens good
candidates who adapt well to ileoanal pouch anastomosis without stoma; body image less affected; operate before patients
lose health insurance
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| Types of colectomy: speaker believes subtotal colectomy with ileorectal anastomosis (IRA) not appropriate; problematic if
patient does not return for surveillance; potential for lawsuit if patient develops rectal carcinoma after IRA; good results from
proctocolectomy with ileal pouch anal anastomosis (IPAA) for FAP include no pouchitis, better function, and fewer bowel
movements (3-4 daily) than those who have same surgery for ulcerative colitis (5-6 bowel movements daily); celecoxib
(Celebrex)—reduces polyp formation only if constantly administered; rapid reformation of polyps if drug discontinued; rectal
mucosectomy with visualization of dentate line— patients need indefinite surveillance of pouch and dentate line to visualize
columnar l (premalignant) epithelium; patients require annual anoscopy or pouchoscopy
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| Ampullary and periampullary malignancies: ampullary carcinoma second-leading cause of death in FAP if colon
not properly treated; 10-yr lag time between formation of colonic polyps (≈16 yr of age) and duodenal polyps (25-30 yr
of age); all FAP patients should have surveillance endoscopy; in speaker’s experience compliance not good; Spiegelman
classification—class 0 or 1, few polyps; class 4, large or “near carpeting” of duodenum with adenomatous polyps; medical
management—nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-2 inhibitors associated
with some regression or slower growth, but discontinuing drugs causes rapid recurrence; other therapies—endoscopic
treatment with snare resection on limited small lesions; widespread ablation of duodenal mucosa using photodynamic
therapy, infrared coagulation, or argon beam coagulation; no data to determine effectiveness or durability of treatment
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| Surgical treatment of duodenal malignancy: perform duodenal resection or transduodenal ampullectomy for isolated
ampullary or few smaller lesions; procedures associated with >60% recurrence at 5 yr, 70% at 10 yr; surgery for
staging or delaying purposes, not curative; pancreaticoduodenectomy (Whipple procedure) definitive treatment; if pancreas
soft, morbidity significant; pancreas-preserving duodenectomy performed on patients with ampullary sparing and
multiple duodenal polyps; gastric polyps and neoplasias worrisome to patient but pathologically benign; duodenal surveillance
to look for gastric neoplasia; few patients develop adenomas, and these can be managed endoscopically; must
distinguish adenomatous polyp from fundic gland polyp
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| Desmoids: nonmetastatic mesenchymal tumors; locally aggressive; occur after surgical trauma; abdominal wall most
common site; occurrence in mesentery causes bowel obstruction, vascular compression and mesenteric vascular thrombosis,
nerve impingement (painful), ureteral obstruction, and hydronephrosis; twice as frequent in women; medical
treatment—NSAIDs, most commonly sulindac (Clinoril); high-dose tamoxifen slows progression or causes regression;
treated with imatinib; Ckit receptor rarely present, but more favorable treatment outcome possible if Ckit present; surgery
recommended for patient with symptoms (usually pain) when medical therapy fails; requires resection with small margin
and often mesh reconstruction; mesenteric involvement often unresectable
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Educational Objectives
| The purpose of this program is to provide the listener with information on management of gastrointestinal cancers.
After hearing and assimilating this program, the clinician will be better able to:
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| Discuss the treatment for patients with colorectal cancer.
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| Summarize the surgical options for patients with gastrointestinal stromal lesions.
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| Review the categories of familial polyposis coli.
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| Discuss the malignancies and treatments related to familial adenomatous polyposis.
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| Describe the management of patients with desmoids.
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Discussed on This Program
Bevacizumab [Avastin]
Celecoxib [Celebrex]
Imatinib mesylate (STI-571) [Gleevec]
Sulindac [Clinoril]
Tamoxifen citrate [Nolvadex]
Suggested Reading
Beham A: Survival benefit in patients after palliative resection vs non-resection colon cancer surgery. World J Gastroenterol
12:6634, 2006; Blanke CD et al: A phase I study of 5-fluorouracil, leucovorin, and celecoxib in patients
with incurable colorectal cancer. Prostaglandins Other Lipid Mediat 75:169, 2005; Cats A: New developments in
systemic chemotherapy in advanced colorectal cancer. Scand J Gastroenterol Suppl 239:78, 2003; Cook AD et al:
Surgical resection of primary tumors in patients who present with stage IV colorectal cancer: an analysis of surveillance,
epidemiology, and end results data, 1988 to 2000. Ann Surg Oncol 12:637, 2005; Cummins ER et al: Incurable
colorectal carcinoma: the role of surgical palliation. Am Surg 70:433, 2004; Delbaldo C et al:
Pharmacokinetic-pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal
stromal tumors. Clin Cancer Res 12:6073, 2006; Demetri GD et al: Efficacy and safety of sunitinib in
patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet
368:1329, 2006; Gallagher MC et al: Pylorus-preserving pancreaticoduodenectomy for advanced duodenal disease
in familial adenomatous polyposis. Br J Surg 91:1157, 2004; Iafrate F et al: Preoperative staging of rectal
cancer with MR Imaging: correlation with surgical and histopathologic findings. Radiographics 26:701, 2006; Joensuu
H: Sunitinib for imatinib-resistant GIST. Lancet 368:1303, 2006; Lassau N et al: Gastrointestinal stromal tumors
treated with imatinib: monitoring response with contrast-enhanced sonography. AJR Am J Roentgenol
187:1267, 2006; Miettinen M, Lasota J: Gastrointestinal stromal tumors: review on morphology, molecular pathology,
prognosis, and differential diagnosis. Arch Pathol Lab Med 130:1466, 2006; Mosolits S et al: Towards
therapeutic vaccines for colorectal carcinoma: a review of clinical trials. Expert Rev Vaccines 4:329, 2005; Murakami
Y et al: Duodenal cancer arising from the remaining duodenum after pylorus-preserving pancreatoduodenectomy
for ampullary cancer in familial adenomatous polyposis. J Gastrointest Surg 9:389, 2005; Nielsen
M et al: Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated
polyposis coli (MAP). J Med Genet 42:e54, 2005; Rothenberger DA: Palliative therapy of rectal cancer. Overview:
epidemiology, indications, goals, extent, and nature of work-up. J Gastrointest Surg 8:259, 2004; Sekine S et
al: High-grade dysplasia associated with fundic gland polyposis in a familial adenomatous polyposis patient, with
special reference to APC mutation profiles. Mod Pathol 17:1421, 2004; Sieber OM et al: Multiple colorectal adenomas,
classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 27:791, 2003; Truta B et
al: A comparison of the phenotype and genotype in adenomatous polyposis patients with and without a family history.
Fam Cancer 4:127, 2005; Wu TJ et al: Surgical treatment and prognostic analysis for gastrointestinal stromal
tumors (GISTs) of the small intestine: before the era of imatinib mesylate. BMC Gastroenterol 6:29, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
Dr. Law has disclosed that he is a consultant for Novartis.
Drs. Gryfe and Law addressed the Update in General Surgery meeting, held April 20-22, 2006, in Toronto, ON and
sponsored by the Department of Surgery, Faculty of Medicine, University of Toronto. Dr. Sharp addressed 35th Annual
Postgraduate Course in Surgery, held April 27-29, 2006, in Charleston, SC, and sponsored by the Medical University
of South Carolina, Department of Surgery. The Audio-Digest Foundation thanks the speakers, the University
of Toronto, and the Medical University of South Carolina for their cooperation in the production of this program.
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