TOPICS IN GASTROINTESTINAL CANCER
| HEPATOCELLULAR CANCER: THE NEW EPIDEMIC —Robert R. Schade, MD, Professor of Medicine and Chief, Section of Gastroenterology/Hepatology, Medical College of Georgia, Augusta |
| Risk factors and prevention of hepatocellular carcinoma (HCC): cirrhosis greatest risk factor; in United States, risk factors include hepatitis C, alcohol abuse leading to cirrhosis, and untreated hemachromatosis; HCC frequently develops from long-term viral infections; hepatitis B—in Asia, chronic hepatitis B main risk factor, even in noncirrhotic patients; 380 million people with chronic hepatitis B (100-fold relative risk of developing HCC); aflatoxin, produced by fungus growing on grains stored in moist area, may increase risk for HCC; hepatitis B vaccination can prevent hepatitis B and HCC (70% of HCC cases associated with hepatitis B); in Europe and United States, hepatitis C major cause of HCC |
| Surveillance and diagnosis: screening—recommend ultrasonography (US) and alpha-fetoprotein (AFP) assay at 6-mo intervals; screen cirrhotic patients, Child’s class A patients, and Child’s class B patients if resectable or if transplantation available; patients with disease classified as Child’s class C eligible only for transplantation (more advanced tumors); identification of lesions—malignancy occurs in <50% of nodules <1 cm in size; diagnosis difficult even with fine needle aspiration (FNA); 1- to 2-cm nodules require positive cytohistology for diagnosis (30%-40% false-negative rate); use noninvasive criteria in cirrhotic patient with tumor >2 cm; make diagnosis if nodule >2 cm, arterial hypervascularization seen using both computed tomography (CT) and magnetic resonance imaging (MRI) or either CT or MRI showing hypervascularization and alpha-fetoprotein >400 mcg/L; imaging methods—gadolinium-enhanced MRI more sensitive and more precise for detecting smaller nodules than helical CT; algorithm—European Association for the Study of the Liver recommends US and AFP in cirrhotic patients at 6-mo intervals; continue if patient has normal AFP and no nodule detected; obtain spiral CT with angiographic contrast if AFP elevated; obtain US at 3-mo intervals if nodule <1 cm detected; continue surveillance if nodule remains unchanged; diagnosis—use FNA to make tissue diagnosis if nodule 1 to 2 cm; obtain AFP, CT, and MRI if nodule ≥2 cm; angiography during CT and gadolinium-enhanced MRI may be useful in visualizing and detecting lesion; 117 days average doubling time of nodule; growth of HCC—metastasis can occur intrahepatically; genetic studies indicate worse prognosis if 2 separate nodules within cirrhotic liver have identical DNA, compared to those with different DNA; tumors can invade biliary system, portal vein, or hepatic veins (associated with worse prognosis); extrahepatic metastasis spreads to lungs, bone, and adrenal glands; evaluate patient with whole-body CT and/or positron emission tomography (PET) for possible metastases |
| Diagnosis: clinical presentation may include polycythemia or hypoglycemia; diagnostic tools include US, CT, MRI, AFP, and liver biopsy; AFP—>400 ng/mL highly suggestive of HCC; patients with incidental HCC found at explant for cirrhosis and liver failure had low AFP levels; rate of increase of AFP controversial issue; keep suspicion high for HCC if patient has hepatitis C and AFP shows rapid increase despite absence of nodule on imaging; liver biopsy—can use CT, US-guided, or FNA |
| Survival rate: 40% to 50% survival in untreated cancers at 1 yr; Cancer of the Liver Italian Program (CLIP) scoring system uses Child-Pugh score (grades A, B, and C have scores of 0, 1, and 2 points), tumor morphology (single nodule and <50% liver involvement has 0 points, multiple nodules and <50% involvement has 1 point, large nodule or >50% of liver involved has 2 points), AFP > 400 ng/mL has 1 point, <400 ng/mL has 0 points, and portal vein thrombosis 0 or 1 point; stage 0 associated with best survival probability; survival diminishes as score increases from 1 to 6 |
| Liver transplantation: criteria—includes tumors <5 cm, ≤3 nodules, lacking extrahepatic spread or invasion of portal vein; study of 48 cirrhotic patients with small unresectable tumors and ≤3 nodules <3 cm in diameter; Child’s class A or B patients underwent chemoembolization while waiting for transplant; 9-54–mo follow-up; 4-yr survival after transplantation 75%, with recurrence-free survival 83%; concluded transplantation viable choice in selected patients; best candidates for transplant have single tumor ≤6.5 cm, and ≤3 nodules <3 cm; Model for Endstage Liver Disease (MELD) score applied to patients seeking donor liver (can calculate MELD score using calculator on United Network for Organ Sharing Web site [www.unos.org]); MELD score based on serum urea nitrogen (BUN), prothrombin time, and bilirubin; typical patient has 24 to 26 MELD score; MELD score correlates with 90-day survival; patients given 24 points for single HCC <2 cm and 29 points for HCC ≤5 cm and ≤3 nodules |
| Surgical resection: <5% of tumors resectable (unresectability due to cirrhosis, size and number of tumors, or involvement of major structures); requires experienced surgical team; treatment of choice in noncirrhotic patients; carefully select patients to avoid treatment-related complications (remnant must be large enough to maintain viability); 5-yr survival 70% |
| Percutaneous treatments: for unresectable tumors; most commonly involves injection of ethanol to kill cells within 1- cm margin around nodule; other methods include radiofrequency ablation (RFA); most studies show ≤50% survival rate in selected Child-Pugh class A patients; usually done using US guidance, but can be done percutaneously or laparoscopically; survival comparable to resection; RFA—5-yr survival estimated at 33% to 40%; factors determining survival include tumor size, morphology, and encapsulation; produces 1-cm ablation ring around tumor; technique involves localizing tumor, introducing probe, deploying ablation needles, and applying RF to produce 1-cm circumferential tissue necrosis |
| Palliative treatment: slowing tumor growth requires embolizing hepatic artery to reduce blood supply to tumor; can also involve intra-arterial chemotherapy using 5-fluorouracil and cisplatin after embolization (regional chemotherapy better tolerated than systemic); partial response rate achieved in 15% to 55% of patients; select candidates with well preserved liver function and asymptomatic multinodular tumors without vascular invasion or extrahepatic spread; exclude patients with liver decompensation (ie, Child-Pugh class C); study comparing embolization to conservative treatment at 1- and 2-yr intervals found survival advantages do not occur until second year |
| Prevention: vaccinate against hepatitis B (in United States, most cases of hepatitis B occur at age of onset of sexual activity); use of antiviral agents to slow progression of hepatitis may not reduce risk for HCC; use iron depletion therapy in hemachromatotic patients |
| Screening: identify patients at risk (eg, cirrhotic patients); screen patients using US and serum AFP at 6-mo intervals (or perform AFP at 6 mo and US at 1 yr and alternate); CT and MRI for screening not shown to improve survival |
| CURRENT ISSUES IN THE SURGICAL MANAGEMENT OF COLON CANCER —John D. Mellinger, MD, Associate Professor of Surgery, Section of Gastrointestinal Surgery, Department of Surgery, Medical College of Georgia, Augusta |
| Local control in rectal cancer: local recurrence rate after surgical resection 25% to 35%; significant morbidity and mortality associated with surgical management; North Central Cancer Treatment Group trial found postoperative adjuvant chemo- and radiotherapy reduced local recurrence rate by ≈50%; subsequent studies suggested preoperative radiotherapy more effective than postoperative (radiation-induced cancer cell injury predicated on good O2 supply to tissues; blood supply before surgery undisrupted and more effective in maintaining O2 supply to cancer cells); Swedish rectal cancer trial suggested preoperative radiotherapy improves survival in patients with rectal cancer |
| Local control after total mesorectal excision (TME): without radiotherapy or adjuvant therapy, Heald found local recurrence rate 5%; other studies found improved local recurrence rates and overall survival associated with TME of rectal cancer; local control rate maintained in surgeons taught TME technique (surgeons who performed >12 cases/yr had local recurrence rate of 4%) |
| TME technique: sharp planar dissection of fascial or perineal condensation layers around mesorectum down to level of levators, with careful preservation of pelvic autonomic nerves, and avoidance of “coning” (often done with simple manual stripping of rectal tissues in low pelvis); identify and preserve layer of visceral peritoneum surrounding mesorectum during entry into presacral space and into anterior space through Denonvilliers’ fascia; compared to wide excision— avoids blunt dissection of rectum along sacrum, double ligation of middle sacral arteries, ligation and transection of lateral rectal ligaments to get into mesorectal plane, disrupting tissue planes where lymphatic channels and tumor cells may lie, and injuring pelvic autonomic nerves running close to middle hemorrhoidal vessels or lateral rectal stalks; wide excision may result in injury of pelvic plexi and result in higher incidence of postoperative bladder and sexual dysfunction; disadvantages—increased anastomotic leak rates in some series; combining radiotherapy and sphincter-preserving surgery may produce functional limitations in first 12 mo after surgery (eg, rectal compliance, soiling, and tenesmus); functional outcome—increased rate of passive incontinence during first 12 mo; increased rate of urgency and tenesmus that improves at 1 yr; changes in postoperative rectal-anal inhibitory reflex and sphincter function demonstrated on manometry; potential for erectile dysfunction (can be improved with newer agents, eg, sildenafil) |
| J-pouch reconstruction of neorectum: prospective studies show improved stool frequency and incontinence in first 12 mo associated with J-pouch reconstruction; improvement in functional outcome similar to ileal pouch-anal anastomosis after total proctocolectomy; technique—segment of colon brought down to residual rectum or anal canal and stapled to rectum with GIA stapling device in J-shape |
| Coloplasty of proximal colon: Heineke-Mikulicz-type plasty with longitudinal division along taenia; transverse closure performed to widen colon above anastomotic area; less effective than J-pouch reconstruction but does show improvement in functional outcome |
| TME and preoperative radiotherapy in rectal adenocarcinoma: prospective randomized study looked at standardized TME and preoperative radiotherapy in 1800 patients with biopsy-confirmed rectal adenocarcinoma in low rectum; patients randomized to receive 25 Gy preoperative radiotherapy over 5 days, followed by TME or TME only; local recurrence rate in combined treatment group 2%; local recurrence rate in patients who had TME only 8.2%; combined treatment group had slightly increased bleeding and perineal wound complication rate; combined treatment had greatest effect in patients with stage II or III disease |
| Laparoscopy and colorectal cancer: early concerns surrounded trocar site recurrences, adequacy of resection, and oncologic outcome |
 | Trocar site recurrence: prospective series do not show increase in local recurrence rate if surgeon follows accepted oncologic techniques; trocar site recurrence rates same as wound recurrence rates after open colectomy (≈1%) |
| Adequacy of resection: randomized studies show same specimen length, same number of lymph nodes evaluated, same length of mesocolon, and same margins obtained in laparoscopic, compared to open procedure |
| Quality of life (QOL): Clinical Outcome of Surgical Treatment (COST) trial evaluated QOL using 3 validated clinical outcome measures and surrogate markers (eg, hospital postoperative analgesic use and length of stay); standardized laparoscopic technique involved intracorporeal mobilization and ligation of primary vascular pedicle, <6-cm incision for extraction of immobilized bowel, and extracorporeal resection and anastomosis; participating surgeons had performed ≥20 laparoscopic colectomies with good oncologic technique and were subjected to video audit on random sample of first 500 cases in trial; data analyzed on intent to treat basis; overall conversion rate 25%; conversion resulted in worse QOL scores; most patients converted because of advanced disease, inadequate visualization, or adhesions; reduction in oral analgesic use, parenteral analgesic use, and length of stay associated with laparoscopic procedure; QOL measures showed no differences between laparoscopic and open procedures at 2 days, 2 wk, or 2 mo in Symptoms Distress Scale (SDS), QOL index, or pain distress scale; global rating scale favored laparoscopic procedure at 2 wk; laparoscopic technique does not improve QOL |
| Intermediate oncologic outcome: study data—prospective study with 6-yr follow-up showed outcome after laparoscopic procedure in patients with Duke’s stages A and B similar to open colectomy, and Duke’s stage C patients had much better oncologic outcome than historical controls; prospective study with 4-yr follow-up showed improved survival after laparoscopic procedure in patients of all disease stages (greatest benefit seen in stage III disease; study results inconclusive (study overestimated expected survival difference, had inadequate number of stage III patients, and adjuvant therapy given more often to laparoscopic patients); study using laparoscopic TME resulted in high morbidity rate and worse functional outcome than with open TME; another study showed significant complication rates when preoperative radiotherapy combined with laparoscopic technique; study looking at consecutive series of patients who underwent laparoscopic surgery found patients who were converted had worse 5-yr survival rates (study had low conversion rate of ≈12%); most patients converted because of obesity or advanced disease) |
| COST outcome data: laparoscopic procedure had similar recurrence rates and similar survival, compared to open procedure in all disease stages, same oncologic outcome, and similar complication and recurrence rates at 4 yr; laparoscopic technique associated with longer operating time, greater number of adhesions, and bowel adhesions in reoperative laparoscopic patients |
| Immunologic issues: study found serum from patients undergoing major open surgery stimulated in vitro growth of colon cancer cells but preoperative serum from those same patients did not; serum from patients undergoing comparable laparoscopic procedures did not stimulate in vitro cancer cell growth; mitogen involved in stimulating cancer cell growth identified as insulin-like growth factor binding protein-3 |
Educational Objectives
| The goal of this program is to educate the listener about hepatocellular carcinoma (HCC) and the current surgical management of colorectal cancer. After hearing and assimilating this program, the clinician will be better able to: |
| 1. Describe the risk factors associated with HCC. |
| 2. Identify the diagnostic criteria for HCC. |
| 3. Manage a patient with an unresectable HCC. |
| 4. Describe the advantages of total mesorectal excision, compared to wide excision in the management of rectal cancer. |
| 5. Compare the effectiveness of laparoscopic colectomy to open colectomy in managing colon cancer. |
Discussed on This Program
Cisplatin (CDDP) [Platinol-AQ] Fluorouracil (5-fluorouracil, 5-FU) [Adrucil, Carac, Efudex, Fluoroplex]
Suggested Reading
Bosch FX et al: Epidemiology of hepatocellular carcinoma. Cli.Liver Dis 9:191, 2005; Bujko K et al: Postoperative complications in patients irradiated pre-operatively for rectal cancer: report of a randomised trial comparing short-term radiotherapy vs chemoradiation. Colorectal Dis 7:410, 2005; Craxi A et al: Prevention of hepatocellular carcinoma. Clin Liver Dis 9:329, 2005; Guillem JG et al: Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg 241:829, 2005; Huang YH et al: Evaluation of predictive value of CLIP, Okuda, TNM and JIS staging systems for hepatocellular carcinoma patients undergoing surgery. J Gastroenterol Hepatol 20:765, 2005; Kanellos I et al: Anastomotic leakage following anterior resection for rectal cancer. Tech Coloproctol 8 Suppl 1:s79, 2004; Kirman I et al: Depletion of circulating insulin-like growth factor binding protein 3 after open surgery is associated with high interleukin-6 levels. Dis Colon Rectum 47:911, 2004; Kirman I et al: Open surgery induces a dramatic decrease in circulating intact IGFBP-3 in patients with colorectal cancer not seen with laparoscopic surgery. Surg Endosc 19:55, 2005; Kirman I et al: Plasma from patients undergoing major open surgery stimulates in vitro tumor growth: Lower insulin-like growth factor binding protein 3 levels may, in part, account for this change. Surgery 132:186, 2002; Marrero JA: Hepatocellular carcinoma. Curr Opin Gastroenterol 21:308, 2005; Maurer CA: Urinary and sexual function after total mesorectal excision. Recent Results Cancer Res165:196, 2005; Michielsen PP et al: Viral hepatitis and hepatocellular carcinoma. World J Surg Oncol 3:27, 2005; Mittal R et al: Accuracy of computerized tomography in determining hepatic tumor size in patients receiving liver transplantation or resection. J Clin Oncol 2:637, 1984; Moradpour D et al: Pathogenesis of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 17:477, 2005; Sherman M: Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis25:143, 2005; Thomas MB et al: Hepatocellular carcinoma: the need for progress. J Clin Oncol 23:2892, 2005; Wong LL et al: Hepatitis B and alcohol affect survival of hepatocellular carcinoma patients. World J Gastroenterol 11:3491, 2005.
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, the faculty reported nothing to disclose.
Drs. Schade and Mellinger were recorded in Sea Island, Georgia, July 26-30, 2004, at Medical and Surgical Approaches to GI Disorders, presented by the Medical College of Georgia School of Medicine, Augusta. The Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation in the production of this program.
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