Colon Cancer in Pregnancy

Colorectal Cancer

1. What every clinician should know

Clinical features and incidence

In women, colorectal cancer (CRC) is the third most common cancer and is the third most common cause of cancer death, following lung and breast. CRC is rare in pregnancy, with a reported incidence of 1/18,000 to 1/50,000 (0.002-0.005%).

Pregnancy-associated cancer refers to the instance when the inital diagnosis of cancer is made during pregnancy or within 12 months of delivery. It is important to realize that cancer is the leading medical cause of death in women of reproductive age. In pregnancy, the incidence rate of cancer reported in the literature has ranged from 0.07-0.1%. However, a recent population-based linkage study by Lee et al demonstrated a higher incidence rate of pregnancy associated cancer, increasing from 112.3 to 191.5 per 100,000 pregnancies between 1994 and 2008, corresponding to a 13.2% to 23.6% increase in women aged 35 and older.

CRC accounts for approximately 15% of all cancers diagnosed in the United States. An estimated 102,480 cases of colon and 40,340 cases of rectal cancer are expected to occur in 2013. Estimates from the American Cancer Society project that 50,830 deaths from CRC are expected to occur in 2013, accounting for 9% of all cancer deaths. Americans have a 5% lifetime risk for CRC.

Incidence of CRC has been declining in the United States by 2-3% per year over the past 15 years, which has been largely attributed to increases in CRC screening that provide for the detection and removal of polyps before they progress to cancer. From 2005-2009 the incidence rates declined by 4.1% per year among adults 50 years of age and older for whom screening is recommended; during that time, CRC rates increased by 1.1% per year for those younger than 50. Mortality rates for CRC have also declined for both men and women over the past two decades, reflecting the declining incidence rates and improvements in early detection and treatment. The rate declined by 3.1% per in women and 2.4% in men from 2005 to 2009.

CRC is rare before 40 years of age in both women and men, with 90% of cases occurring after 50 years of age. Given the median age of diagnosis, it is not surprising that CRC in pregnancy is rare. The mean age of diagnosis of CRC during pregnancy is 31 years (range 16-48). Most cases of CRC in pregnancy are rectal carcinomas, as 86% of CRCs diagnosed in pregnancy were below the peritoneal reflection in one review. This may reflect a detection bias due to rectal exams performed during routine antenatal care.

The pathogenesis of CRC is that of an adenomatous polyp that slowly increases in size, becomes dysplastic and evolves into cancer. Adenomatous polyps can become malignant over 5 to 20 years. Characteristics of higher propensity for malignancy include villous histology, greater than 1cm in diameter and a high grade of dysplasia. Poor prognosis is associated with colloid and signet ring subtypes of adenocarcinoma, which together represent approximately 20% of tumors.

A possible association between neoplastic cell growth and proliferation and gestation may have a role in the pathogenesis of CRC in pregnancy. Factors such as pregnancy hormones (estrogen, progesterone), p53 protein abnormality and cyclooxygenase enzyme have been implicated in the carcinogenesis of CRC in pregnancy. However, further information is required.

Signs

pallor
abdominal mass
small bowel obstruction (lesions obstructing the ileocecal valve)
blood on rectal exam
palpable mass on rectal exam
cachexia
palpable liver, fistulae (bladder, vaginal) with tumor invasion to adjacent organs
perforation with peritonitis
ascites
jaundice, icterus

Symptoms

Common: Due to the physiologic changes of pregnancy, symptoms of CRC may be mistaken for symptoms of normal pregnancy. Presentation of CRC in pregnancy is commonly Duke’s class B or greater, likely due to delayed diagnosis.

Symptoms vary according to the anatomic location of the primary tumor. In general, symptoms are attributable to either colonic obstruction or anemia secondary to gastrointestinal bleeding. Common presenting symptoms include rectal bleeding with or without anemia, abdominal pain and change in bowel function. These symptoms are also shared with those of healthy pregnancies due to the physiological changes that occur.

Systemic disease: May be reflected with weight loss, anorexia, nausea/vomiting and symptoms related to hepatic dysfunction (jaundice, icterus, and ascites). In pregnancy, lethargy, nausea, change in bowel habits, physiologic anemia and dyspnea are common, and may decrease the index of suspicion for malignancy.

Right-sided colonic lesions: Obstructive symptoms or changes in bowel habits are rarely noted in right sided lesions as stool is relatively liquid as it passes through the ileocecal valve into the right colon. Patients with right-sided lesions present with symptoms due to anemia, including weakness, dyspnea on exertion, palpitations and lethargy.

Left-sided colonic lesions: Due to narrowing of the bowel lumen, altered bowel habits may be noted, most commonly new constipation or change in the caliber of stool. As narrowing progresses, diarrhea and frequent bowel movements may occur.

Bleeding per rectum, tenesmus, and cramping abdominal pain may be observed. Rectal bleeding due to hemorrhoids is common in pregnancy, as is constipation (more so in the first trimester).

Metastatic disease: Weight loss, anorexia, dyspnea (pulmonary metastases), jaundice (liver metastases) and pain due to extension of the tumor to adjacent organs or liver metastases may be observed.

Risk factors

Patients at increased risk for CRC include those with a:

History of adenomatous polyps.
Personal history of curative-intent resection of CRC.
Family history of CRC in a first-degree relative before 60 years of age.
Family history of colorectal adenomas in a first-degree relative before 60 years of age.
Long standing history of inflammatory bowel disease.
Diagnosis or suspicion of hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome).
*Familial adenomatous polyposis (FAP).
*Gardner’s syndrome.
*Peutz-Jeghers syndrome.

*Of note, the hereditary syndromes represent only a small portion of colorectal cancers diagnosed in pregnancy.

2. Diagnosis and differential diagnosis

Diagnostic criteria

Symptoms suggestive of gastrointestinal pathology need to addressed in pregnancy, regardless of the trimester. Referral to a specialist in gastroenterology is advised.

Screening

Screening should be performed prior to conception when indicated.

Screening onset for CRC is determined after a patient’s individualized assessment of risk for colon cancer is made.

For patients at average-risk, initiation of screening should begin at 50 years of age. For high risk patients screening should start at 40 years of age or 10 years younger than the age at which the youngest affected relative was diagnosed with CRC.

Stool-based tests, flexible sigmoidoscopy or colonoscopy are recommended as screening tests in patients who are at average risk.

Diagnosis

Evaluation for CRC in pregnancy is similar to that in the nonpregnant patient, with some modifications that take into consideration the impact on the fetus.

Diagnosis of CRC in pregnancy is based on the physical exam, endoscopic biopsy and abdominal imaging.

The physical exam should address the following:

General inspection: Conjunctival pallor, cachexia.
Palpation of supraclavicular lymph nodes – involvement of the supraclavicular LN is consistent with stage IV disease. Enlargement of the left supraclavicular lymph node secondary to gastrointestinal cancer (Virchow’s node) results from metastasis along the cisterna chyli to the left thoracic duct.
Abdominal exam: Will be limited by the gravid uterus. Inspect and percuss for ascites. Palpate the abdomen for a mass and for enlarged liver with an irregular edge. Palpate for tenderness, which may be associated with liver metastases or perforated cancer.
Perform a rectal exam: Check for blood. Check for a palpable rectal tumor, assess for fixation of the rectovaginal septum.
Digital rectal exam and sigmoidoscopy can reveal more than 80% colorectal tumors in pregnant women.
Laboratory assessment: Complete blood count, basic metabolic panel, hepatic function panel and carcinoembryonic antigen (CEA). Serum CEA levels have been demonstrated to increase throughout pregnancy, but levels remain within the normal reference range.
Colonoscopy should be considered and is the gold standard investigation.

Colonoscopy of the entire colon to assess for other synchronous lesions is advised in the non-pregnant population (up to 5% patients have another focus of CRC in their bowels). While an increased propensity of rectal carcinomas have been observed to arise in pregnancy, the decision to perform sigmoidoscopy versus colonoscopy should be based on findings on physical exam, ancillary test results and concern for synchronous lesions.

Colonoscopy:CRC is commonly diagnosed during colonoscopy with biopsy. This method is potentially curative when benign polyps and carcinoma in situ are excised. Diagnosis will depend on tissue pathology.

The Practice Committee of the American Society of Gastrointestinal Endoscopy (2012) published guidelines for performing endoscopy in pregnancy that support endoscopy in pregnancy when a strong indication exists. The procedure should be deferred until the second trimester when possible

Risks of the endoscopy include those that are inherent with the procedure itself (perforation, bleeding, abdominal pain, among others), and also include potential fetal effects secondary to maternal hypotension, hypoventilation, medication exposure and placental abruption from mechanical pressure applied to the uterus. Thus, optimizing maternal condition during the procedure with left lateral uterine displacement, close attention to maternal vital signs and careful selection of medications during the procedure should minimize untoward maternal and fetal effects.

Use of anesthesia services should be considered if available and is recommended, particularly when deep sedation is needed.

Preoperative obstetric consultation is advised.

The decision to monitor the fetal heart rate should be individualized and will depend on the gestational age of the fetus and available resources.

Endoscopy is contraindicated in placental abruption, imminent delivery, ruptured membranes or uncontrolled eclampsia.

Imaging

Radiographic imaging is an important tool in the management of CRC for the evaluation of metastatic disease. In pregnancy, procedures not associated with ionizing radiation are preferred to limit fetal exposure (e.g. ultrasonography, MRI) and should be used when appropriate.

Ionizing radiation can result in teratogenic effects and cell death, carcinogenesis, and genetic effects or mutations in germ cells. There is little or no information to estimate the frequency or magnitude of adverse genetic effects on future generations.

Computed tomography (CT)

In nonpregnant patients abdominal CT is the preferred imaging modality to facilitate clinical staging.
Abdominal/pelvic CT may deliver 25-45 mGy (2.5-4.5 rads) of ionizing radiation.
The radiation dose of pelvic CT is likely below the estimated threshold level for induction of congenital malformations (5-15 rads).
The carcinogenic risk to the fetus increases very slightly with in utero exposure to ionizing radiation. Pelvic CT may increase the risk of fatal childhood cancer twofold; however, the baseline risk of fatal childhood malignancy is low (1/2,000). Therefore, the increased risk of fatal childhood malignancy with pelvic CT of 2/2,000 after exposure to 5 rads remains low.
In specific cases in which a patient may have been exposed to a series of ionizing studies, an expert in dosimetry calculations may be helpful in calculating estimated fetal dose.

Ultrasonography: Hepatic has been demonstrated to be sensitive for detecting liver metastases in pregnancy.

Whole Body MRI may be utilized as an adjunct to clinical staging and should be considered when possible in lieu of CT when appropriate.

Differential diagnosis

Colitis, from inflammatory bowel disease (Crohn’s disease, ulcerative colitis), ischemia, or infectious causes.
Diverticular disease.
Other colorectal tumors – polyps, adenomas, carcinoid tumors, lymphomas, metastatic disease from other sites, mesenchymal tumors, and squamous cell carcinomas (anus or anorectal junction).
Hemorrhoids.
Perforated appendix.
Extrinsic tumors – ovarian tumors or cysts, uterine myomas.
Upper gastrointestinal tract disease – biliary or gastroduodenal disease, peptic ulcer disease.
Irritable bowel syndrome.

3. Management

Prior to conception

Preconception counseling should be strongly considered by patients with a personal history of CRC or strong family history of CRC suggestive of a familial colon cancer syndrome. The counseling should address maternal and fetal complications with potential pregnancy and genetic aspects. The familial cancer syndromes include FAP, juvenile polyposis syndrome (JPS) and HNPCC. Prenatal diagnosis (PND) and pre-implantation genetic diagnosis (PGD) are available for hereditary cancer syndromes in most European countries; however social, ethical and political controversy remain.

Given the rapidly evolving realm of genetics, genetic counseling should be considered to provide the patient with the most current information regarding available PND and PGD to help the patient in her decision making regarding family planning.

Antenatal

There are no universally accepted guidelines for treatment of CRC in pregnancy. A multidisciplinary approach is required. After CRC has been diagnosed, management will be guided by the gestational age of the pregnancy and the clinical stage of the malignancy. Treatment of CRC in pregnancy follows the same general guidelines as for non-pregnant patients.

Treatment for various stages of colon cancer:

Stage 0 – polypectomy/surgical resection

Stage I – surgery alone

Stage II – surgery +/- chemotherapy

Stage III – surgery +/- chemotherapy

Stage IV – Palliative chemotherapy, metastasis resection (limited cases)

Patients with bowel obstruction and perforation require immediate hospitalization and intervention.

Before 20 weeks gestation

Prior to viability, the patient will need to determine if she desires to continue or pursue treatment while in the gravid state. Stage for stage, outcomes in pregnancy are similar to those outside of pregnancy. Limits of viability should be discussed.

Primary surgical resection should be performed when the cancer is diagnosed during the first half of the pregnancy, as tumor progression may occur without treatment. Surgery can often be performed without removing the gravid uterus. Primary resection and anastomosis are advised. Hysterectomy is generally not required for colon or rectal resection; however, it may be required to facilitate access to the rectum when needed for intraoperative exposure, when the mother’s life expectancy is less than the time needed to achieve viability, or when the cancer extends to the uterus. Otherwise, when the cancer appears resectable, curative surgery should be performed leaving the pregnancy intact.

After 20 weeks gestation

Abdominal procedures performed late in pregnancy may be associated with preterm delivery and attendant complications. Delaying surgery permits fetal maturity and facilitates surgical exposure and dissection after delivery. However, delay may allow tumor progression. The delay should be minimized as much as possible, with the best interest of the mother and fetus in mind. Surgery should ideally be delayed until fetal viability is reached and when risks of prematurity are considered acceptable to the patient. If delayed, the patient should be informed of the risks of tumor progression and expected risks of fetal prematurity at the gestational age of delivery before making a decision to postpone surgery.

Outside of pregnancy, surgery is undertaken with the intent of cure in 75% of those with CRC. The remainder will require surgery to prevent obstruction, perforation or bleeding.

Ovarian metastases are reported in 25% of pregnant patients, versus 3-8% in non-pregnant patients. Prophylactic bilateral salpingo-oophorectomy simultaneously with resection may be associated with an increased risk for spontaneous abortion, particularly in the first trimester. Bilateral wedge biopsies of the ovaries may be performed during surgery for pathologic examination and subsequent removal if the ovaries are involved, or if hysterectomy is performed for other reasons.

Adjuvant chemotherapy

Delaying chemotherapy until the second or third trimesters is recommended.

Adjuvant chemotherapy is administered to prevent relapse of CRC, which occurs mainly at distant sites. There is controversy over adjuvant chemotherapy in stage II disease because the 5-year survival rate is 75-80% and the reduction in deaths is predicted to be small. The current focus is on finding subgroups of patients with stage II disease who are more likely to benefit from treatment.

Stage III is treated with chemotherapy. Choice of chemotherapy in stage III is FOLFOX (oxaliplatin, infusional 5-FU and leucovorin).

5-FU: The most commonly used agent is 5-fluorouracil, a pyrimidine analog specific for the S-phase of the cell cycle. Information regarding exposure to chemotherapy in pregnancy is derived from case reports and this is limited. First trimester exposure 5-FU has been associated with miscarriage and growth restriction of normal live infants. Exposure in the second and third trimesters has been associated with growth restriction of the fetus and transient toxicity signs in the newborn.

Oxaliplatin: Oxaliplatin is a third-generation platinum analog that appears to act on tumor cells by forming DNA adducts. The use of other platinum agents in pregnancy has been associated with reports of IUGR, fetal demise, newborn hearing loss and fetal ventriculomegaly. Oxaliplatin has not been studied in pregnant women.

Staging

CRC staging is through the American Joint Committee on Cancer (AJCC) TNM system, which uses the degree of tumor invasion, the presence of positive lymph nodes and the presence of distant metastases to classify the disease to one of four stages. Although the AJCC TNM staging system is the preferred staging sytem today, the Duke staging system with the Astler-Coller modification is often referred to in older literature. (See Table I)

Table In

Staging of colorectal cancer AJCC RNM system and Duke equivalents

Tumor

Tis: Carcinoma in situ: intraepithelial or invasion of the lamina propria

T1: Invasion of the submucosa

T2: Invasion into the muscularis propria

T3: Invasion through the muscularis propria into the subserosa

T4: Invasion through visceral peritoneum or into adjacent organs

Node

N0: No lymph node metastases

N1: Metastases in one to three lymph nodes

N2: Metastases in four or more lymph nodes

Metastases

M0: No distant metastases

M1: Distant metastases present

Antenatal checklist

Consultation with gastroenterology, surgical oncology, oncology
Genetics consultation if appropriate
Fetal growth scans
Nutrition consult
Multidisciplinary collaboration to determine optimal time and mode of delivery
Anesthesia consultation
NICU consultation
Social work, chaplaincy, psychology, psychiatry support as needed
Dosimetry calculations to determine total delivered fetal dose if indicated

Intrapartum and postpartum

Mode of delivery may be guided by obstetric indications; however, elective cesarean is often desired as colonic resection and staging procedures can be done concurrently. If a cesarean is required for obstetric reasons, proceeding with resection of the cancer should be considered if the patient is medically stable, no significant complications of cesarean have occurred and exposure is adequate. Proctectomy should be delayed. If surgery is delayed, the procedure should be deferred until after the gravid uterus and pelvic vascularity have regressed to improve accessibility to the tumor and to reduce the risk of bleeding and thromboembolic complications.

Rectal tumors: Cesareans should be considered for large distal rectal tumors obstructing the birth canal or when the tumor is on the anterior rectal wall, as birth trauma or episiotomy may result in entering the tumor.

The placenta should be examined histologically in all cases of maternal malignancy.

Breastfeeding while receiving chemotherapy is contraindicated. Concentrations of chemotherapeutic agents in breast milk are variable and depend on the dose and timing of drug administration. Neonatal neutropenia has been reported in an infant breastfed during maternal treatment with cyclophosphamide.

4. Complications

Maternal complications

Maternal complications include:

Hemorrhage, obstruction and perforation. These conditions may required immediate surgical intervention. Decompressive measures should be used as initial therapy in patients with bowel obstruction or perforation. During the first half of pregnancy, resection and stoma have been recommended with rectal carcinoma diagnosed early in pregnancy. Hartmann’s operation may be performed in patients with obstruction due to rectal cancer early in pregnancy.
Nutritional deficiencies caused by the tumor or chemotherpay induced anorexia.
Depression.

Fetal complications

Fetal risks of CRC include still birth, intrauterine growth restriction, prematurity or termination. One case of placental metastases has been described. The newborn was not affected and was normal, without evidence of tumor at 8 months of age. The effects of chemotherapy in the fetus resemble those in the mother (myelosuppression, ototoxicity).

Use of chemotherapy during the first trimester increases the risk of spontaneous abortion, fetal death and major malformations. The direct effect of the tumor sometimes confounds the risks of fetal loss. Malformations reflect the gestational age at exposure, with particular vulnerability with exposure 2-8 weeks post conception during organogenesis. After organogenesis, the eyes, genitalia, hemopoietic system and CNS remain vulnerable to continued exposure.

In general, chemotherapy should be instituted during pregnancy rather than waiting until after delivery if indicated unless delivery of the newborn can be accomplished within a few weeks of diagnosis, as this may be more acceptable than an extremely preterm birth. Early delivery to avoid fetal exposure to maternal chemotherapy is reasonable if fetal lung maturity can be documented and the fetus is close to term.

Delivery should be avoided during the time of maternal nadir, approximately 2-3 weeks after treatment. To allow for fetal drug excretion via the placenta, chemotherapy administration should be avoided within 3 weeks of anticipated delivery and should not be administered after 35 weeks gestation due to the risk of spontaneous preterm labor. The ability of the fetus/newborn to metabolize the drugs is less than the maternal and placental compartments, particularly in the preterm infant, in whom the hepatic and renal systems are immature.

5. Prognosis and outcome

Maternal prognosis

Stage for stage the survival data are similar for pregnant and non pregnant women with CRC. Outcomes in pregnancy have generally been poor, which may be due to advanced stage at diagnosis, or delay in pursing surgery or administering chemotherapy. Biological changes in pregnancy may affect CRC progression (the influence of estrogen and progesterone receptors or increased level of cyclooxygenase-2 on cancer cell proliferation and metastases).

Advanced metastatic disease is associated with a poor prognosis, with a 5-year survival of 5-8%. The median survival of patients with advanced disease has increased from 10-12 months to 24 months since the introduction of capecitabine, irinotecan and oxaliplatin, and with the approval of two biologic agents, bevacizumab and cetuximab.

Fetal prognosis

Fetal prognosis depends on the pathologic stage of the maternal cancer, gestational age at diagnosis, type and timing of therapy, and timing of delivery.

Data available on long term effects of in utero exposure to chemotherapy is limited. Aviles et al reported described 84 children with a mean long term follow-up of 18.7 years (range 6-29 years) after in utero exposure to chemotherapy for hematological malignancies in pregnancy. Growth, development, educational performance and behavior was normal in these children. Furthermore, 12 second generation children were observed who did not manifest congenital abnormalities, nor was there development of acute leukemia or solid tumors.

No data regarding long term exposure for CRC in pregnancy is available.

Summary

The prognosis for pregnancy associated colon cancer is poor, though outcomes are similar to those occurring outside of pregnancy. Data available on pregnancy outcomes and management are largely based on case reports and series and no formal guidelines exist to direct management.

A thoughtful approach is required that considers the patient’s personal value system regarding her health and that of her fetus as treatment options are discussed.

A multidisciplinary approach is required throughout pregnancy, requiring collaboration between the obstetric, surgical, oncology, neonatology and pediatric teams, as well as social workers, chaplains and ethicists.

6. What is the evidence for specific management and treatment recommendations

“ACOG: Guidelines for diagnostic imaging in pregnancy”.

Aviles, A, Neri, N. “Hematological malignancies and pregnancy: a final report of 84 children who recived chemotherapy in utero”. Clinical Lymphoma. vol. 2. 2001. pp. 173-7.

Bernstein, MA, Madoff, RD, Caushaj, PF. “Colon and rectal cancer in pregnancy”. Dis Colon Rectum . vol. 36. 1993. pp. 172-8.

Cappell, MS. “Colon cancer during pregnancy”. The gastroenterologist's perspective. Gastroenterol Clin North Am. vol. 27. 1998. pp. 225-56.

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Cappel, MS. “The safety of gastrointestinal endoscopy in high risk patients”. Dig Dis. vol. 14. 1996. pp. 228-44.

Cardonick, E, Iacobucci, A. “Use of chemotherapy during human pregnancy”. Lancet Oncol. vol. 5. 2004. pp. 283-91.

Gensheimer, M, Jones, C, Graves, C, Merchant, N, Lockhart, AC. “Administration of oxaliplatin to a pregnant woman with rectal cancer”. Cancer Chemotherapy and Pharmacology. vol. 63. 2009. pp. 371-3.

Girard, RM. “Carcinoma of the colon associated with pregnancy: report of a case”. Dis Colon Rectum. vol. 24. 1981. pp. 473-5.

Lee, Y, Roberts, CL, Dobbins, T, Stavrou, E, Black, K. “Incidence and outcomes of pregnancy-associated cancer in Australia, 1994-2008: a population-based linkage study”. BJOG. 2012. pp. 1572-82.

Nesbitt, JC, Moise, KJ, Sawyers, JL. “colorectal carcinoma in pregnancy”. Arch Surg. vol. 120. 1985. pp. 636

Qaseem, A, Denberg, TD, Hopkins, RH. “Screening for Colorectal Cancer: A Guidance Statement From the American College of Physicians”. Ann Intern Med. vol. 156. 2012. pp. 378-86.

“Practice Committee of the American Society of Gastrointestinal Endoscopy”. Gastrointestinal Endoscopy. vol. Vol 76. 2012.

Walsh, C, Fazio, VW. “Cancer of colon, rectum and anus during pregnancy”. The surgeon's perspective. Gastroenterol Clin North Am. vol. 27. 1998. pp. 257-67.

Nelson, H, Petrelli, N, Carlin, A. ” National Cancer Institute Expert Panel. Guidelines 2000 for colon and rectal cancer surgery”. J Natl Cancer Inst. vol. 93. 2001. pp. 583-96.

Tjandra, JJ, Kildenny, JW, Buie, WD. “The Standards Practice Task Force; The American Society of Colon and Rectal Surgeons. Practice parameters for the management of rectal cancer (revised)”. Dis Colon Rectum. vol. 48. 2005. pp. 1001-12.

Benson , AB, Schrag, D, Somerfield, MR. “American Society of Clinical Oncology Recommendations on adjuvant chemotherapy for stage II colon cancer”. J clin Oncol. vol. 22. 2004. pp. 3408-19.

Davila, RE, Rajan, E, Adler, D. “ASGE guideline: the role of endoscopy in the diagnosis, staging, and management of colorectal cancer”. Gastrointest Endosc. vol. 61. 2005. pp. 1-7.

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