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Regression of Colorectal Adenomas With Intravenous Cytotoxic Chemotherapy in a Patient With Familial Adenomatous Polyposis

Department of Internal Medicine, Division of Hematology/Oncology, Hereditary Cancer Institute, and Colorectal Surgery, Creighton University Medical Center, Omaha, NE

To the Editor:

In the United States, colorectal cancer (CRC) is second only to lung cancer as the leading cause of cancer death.¹ The risk of developing CRC is influenced by both environmental and genetic factors. Familial adenomatous polyposis (FAP) and its variants account for less than 1% of CRC cases. However, among those FAP patients lacking prophylactic colectomy, approximately 90% to 100% will develop CRC by age 45 years.²

FAP occurs in approximately 0.01% to 0.03% of live births. Polyposis usually develops in the second or third decade of life, and it affects both sexes equally. FAP is an autosomal-dominant disorder caused by germline mutations in the adenomatous polyposis coli (APC) gene that is located on chromosome 5q21-q22.^2-4

More than 300 APC gene mutations (mostly frame shifts or premature stop codons resulting in a truncated APC gene) associated with FAP have been described.⁵ The function of the APC gene product is now being elucidated. This inherited germline mutation predisposes patients to hundreds of colonic adenomatous polyps.² Management usually includes prophylactic proctocolectomy or colectomy followed by sigmoidoscopic surveillance and rectal polypectomy. There is some evidence that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenase (COX) -2 inhibitors and sulindac may have a protective effect on the development of colon cancer and lead to the regression of colorectal adenomas. However, once these medications are discontinued, polyp recurrence is rapid, and cancer may occur even in the presence of polyp regression.^6-9

We present a case of a 45-year-old woman with FAP with liver metastasis who showed marked regression of her colonic adenomas after intravenous cytotoxic chemotherapy.

Methods
We reviewed the literature using PubMed and MEDLINE by searching all citations dealing with colonic adenomatous polyp regression in the English language, available from 1966 to the present. Search terms included "polyps," "regression," "chemotherapy," "colorectal adenomas," and "polyposis." We present a case of a woman with FAP with liver metastasis who showed marked regression of colonic polyps after intravenous cytotoxic chemotherapy. The colonic adenoma regression was verified by serial colonoscopies and examination of the surgical specimen.

Results
This 45-year-old white woman had a history of chronic low back pain and iron deficiency anemia when she presented to Creighton University Medical Center complaining of decreased energy, increased fatigue, and shortness of breath. She was amenorrheic and denied any melena, hematochezia, or hematemesis. Her hemoglobin was 6.3 g/dL and hematocrit was 20.4%. She underwent esophagogastroduodenoscopy that revealed mild gastritis and distal esophagitis, as well as excessive bile reflux into the stomach. A colonoscopy demonstrated several hundred 3-mm and 1- to 1.5-cm colonic adenomas (Fig 1). A biopsy of a polypoid necrotic mass that obstructed the lumen of the proximal descending colon showed adenocarcinoma. Computed tomography scan of the abdomen and pelvis was normal. Carcinoembryonic level was 5.5 ng/mL.

View larger version (117K): [in this window] [in a new window]   Fig 1. The first colonoscopy at the time of diagnosis demonstrating hundreds of adenomas.

The patient was initially treated with five cycles of irinotecan, leucovorin, and bolus fluorouracil chemotherapy for the metastatic colon cancer. An interval colonoscopy revealed regression of polyps in both numbers (< 100) and size. Secondary to side effects, the patient was then started on irinotecan, leucovorin, and continuous infusion fluorouracil chemotherapy. After nine cycles of this treatment, a repeat colonoscopy demonstrated only four polyps that were 3 mm in size (Fig 2), which showed significant regression in both size and numbers of colonic polyps from the initial colonoscopy, and serial liver ultrasounds showed marked tumor regression. The same colorectal surgeon performed all of the patient's colonoscopies.

View larger version (131K): [in this window] [in a new window]   Fig 2. The last colonoscopy after receiving chemotherapy showing reduction of number and size of adenomas.

There is a large body of research that has demonstrated that NSAIDs such as sulindac and COX-2 inhibitors contribute to regression of colorectal adenomas. However,once the medications are discontinued, rapid recurrence of adenomas has been reported.^6,7,9,10

Gastroduodenal polyps are associated with FAP patients who have mutations in the APC gene and are associated with an increase in the incidence of duodenal and periampullary cancer. However, NSAIDs or COX-2 inhibitors have been unsuccessful, with few exceptions, in treating gastric and small-bowel adenomas associated with FAP. Further investigation might be considered to see if intravenous chemotherapy can cause a remission of gastric and small bowel adenomas.^11-13

There has been one study done of local chemotherapy for rectal polyposis. Four patients were treated with fluorouracil rectal suppositories. One patient's rectal polyps were reduced without any side effects, but the suppository regimen had to be discontinued in the other three patients secondary to rectal urgency.¹⁴

Recently, there was a case report published, on a patient with cap polyposis who was treated with a single infusion of infliximab 5 mg/kg and who demonstrated dramatic symptomatic improvement.¹⁵ Cap polyposis is characterized by rectosigmoid polyps that have tortuous elongated crypts and are covered by a cap of fibropurulent exudate. The pathogenesis is unknown, but the histology suggests that mucosal prolapse may play a role. The current therapy often used for inflammatory bowel diseases has frequently been ineffective. Overall, infliximab lead to symptomatic improvement and histologic resolution of the polyps.¹⁵

To our knowledge, our patient is the first to have demonstrated marked regression in size and number of polyps per serial colonoscopies while being treated with intravenous cytotoxic chemotherapy for metastatic CRC secondary to FAP. It is difficult, if not impossible, to distinguish whether just one of the chemotherapeutic agents would have led to the polyp reduction or if it was due to the combination of two or three and thereby may have acted synergistically.

Our patient was unusual in that she had classical FAP with the APC germline mutation and presented with metastatic CRC (stage 4) requiring chemotherapy, and her right and transverse colon were not removed surgically. This enabled documentation of polyp regression with serial colonoscopies in response to the intravenous chemotherapy.

Administering toxic chemotherapy for benign polyps could have adverse effects on patients and should be used with caution. However, some patients may have polyps that are surgically challenging to remove because of either the size or location of the polyps (such as those in the duodenum or papillary duct). It may be helpful to obtain case studies of patients in similar circumstances as our patient and/or to create an animal model for further investigation. Depending on the results, then utility of chemotherapy in these situations could be considered for investigation. Further research is merited with respect to chemotherapeutic effects on colonic and gastroduodenal polyps.

Authors' Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Peter T. Silberstein Pfizer (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

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11. Watanabe H, Enjoji M, Yao T, et al: Gastric lesions in familial adenomatosis coli: Their incidence and histologic analysis. Hum Pathol 9:269-283, 1978[Medline]

12. Alexander JR, Andreas JM, Buchi K, et al: High prevalence of adenomatous polyps of duodenal papilla in familial adenomatous polyposis. Dig Dis Sci 34:167-170, 1989[Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jones, D. H. Articles by Ternet, C. Search for Related Content PubMed PubMed Citation Articles by Jones, D. H. Articles by Ternet, C. Social Bookmarking                            What's this?