Advances in the Treatment of Colorectal Disease

Educational Objectives

The goal of this program is to improve treatment of colorectal cancer utilizing adjuvant chemotherapy and the surgi­cal management of rectal prolapse. After hearing and assimilating this program, the clinician will be better able to:

1.   Explain the importance of adding oxaliplatin to a 5-fluorouracil (5-FU) regimen for patients with stage III colorectal cancer.

2.   Identify patients with stage II colorectal cancer who are candidates for adjuvant chemotherapy, including those with stage IIB disease.

3.   Recognize the risk factors for rectal prolapse.

4.   Discuss appropriate studies for presurgical workup of patients with rectal prolapse.

5.   Determine which patients are candidates for abdominal vs perineal repair of rectal prolapse, and list the advan­tages and disadvantages of both types of procedures.

Faculty Disclosure

In adherence toACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Ryan is a consultant for sanofi-aventis. Dr. Cosman and the planning committee reported nothing to disclose. In his lecture, Dr. Cosman discussed the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Ryan spoke at Advances in Colorectal Surgery, held April 17-18, 2009, in Boston, MA, and sponsored by Harvard Medical School. Dr. Cosman was recorded at the Annual San Diego Postgraduate Assembly in Surgery, held March 2-6, 2009, in San Diego, CA, and sponsored by the University of California, San Diego. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Adjuvant Treatment for Colorectal Cancer

David P. Ryan, MD, Clinical Director, Gastrointestinal Cancer Center, Massachusetts General Hospital, Bos­ton, MA

Stage of colorectal cancer at first presentation: as of 1998, 15% of patients presented in stage I, 20% to 30% in stage II, 30% to 40% in stage III, and 20% to 25% in stage IV; currently, more patients appear to be presenting in stages I and II, but good data lacking

Most significant changes of last 10 yr: in speaker’s opinion, earlier presentation and increased number of elderly pa­tients with advanced disease asking for chemotherapy; no good data on tolerance of chemotherapy in patients aged >80 yr

Infusion pumps: European experience showed use of pumps for 5-fluorouracil (5-FU) administration more effec­tive and better tolerated than conventional methods used in United States; infusions now given to most patients with colorectal cancer who require 5-FU; also called de Gramont or folinic acid, oxaliplatin, and 5-FU (FOLFOX) regimen; leucovorin also used; oxaliplatin enhances action of 5-FU

Studies of adjuvant therapy for stage III colorectal cancer

Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Can­cer (MOSAIC): patients randomized to FOLFOX or 5-FU and leucovorin for 6 mo; both regimens delivered via similar infusion schedule; FOLFOX associated with modest (2.5%) increase in overall survival; addition of ox­aliplatin improved survival 4.5% among patients in stage III; for patients with N2 disease (stage III with >4 pos­itive nodes), risk for recurrence with FOLFOX 40%; probability of cure 60%; surgeons should consider 12 cycles of FOLFOX for patients without comorbidities; FOLFOX now considered standard of care for patients with stage III disease

Ongoing studies: National Surgical Adjuvant Breast and Bowel Cancer Project (NSABP) C-08 compared treatment of stage III disease with antibody to vascular endothelial growth factor (anti-VEGF) bevacizumab (Avastin) plus FOLFOX to FOLFOX alone; anti-VEGF already shown to improve survival in metastatic colon cancer; major drawback associated with bevacizumab slightly increased risk for sudden death due to hemorrhage or ar­terial thrombosis; in Avastin Adjuvant (AVANT) study, patients randomized to FOLFOX alone, FOLFOX with bevacizumab, or capecitabine (oral 5-FU plus oxaliplatin [Xelox]) plus bevacizumab); results not yet pub­lished; outcomes may determine role (if any) of bevacizumab in adjuvant treatment of colorectal cancer

Cetuximab (Erbitux): epidermal growth factor (EGF) antibody; effective, but only on tumors with unmutated (wild-type) KRAS gene; »50% of colon cancers have mutation in KRAS; study now ongoing comparing FOLFOX to FOLFOX plus cetuximab as adjuvant therapy for patients with wild-type genotype

Adjuvant treatment of stage II colorectal cancer: depends on oncologist’s preference; patients in stages IIA and IIIA respond similarly; stage IIB heterogeneous; described as T4N0; T4A  —  tumor attached to pelvic wall, blad­der, or other structure; T4B  —  involves visceral peritoneum; prognosis worse than that for T4A (worse prognostic factor than being node-positive); patients with stage IIIA routinely receive chemotherapy, with »10% increase in survival rates over patients in stage II, not all of whom receive chemotherapy

Candidates for adjuvant chemotherapy: those with T4 disease; perforation or obstruction of colon; inadequate lymph node sampling (always insist on 12 nodes whenever possible; 8 nodes inadequate; poorly differentiated histology less important than commonly believed; prognostic value of lymphatic or vascular invasion disappears on multivariate analysis if enough lymph nodes sampled; in analysis of 35,787 cases (stage II, T3N0), probability of 5-yr survival 50% when 1 to 7 nodes examined, »60% when 8 to 12 nodes examined, 65% with >13 nodes ex­amined, and »90% with >20 nodes examined; suggests staging issue

Molecular markers: microsatellite instability  —  good prognostic factor (eg, hereditary nonpolyposis colorectal can­cer [HNPCC]); microsatellite stability suggests poor prognosis; chromosome 18q allelic loss  —  with loss of het­erozygosity (LOH) at 18q, “might as well have stage III disease”; Eastern Cooperative Oncology Group study 5202  —  looking at prognostic value of molecular markers in stage II patients; must enroll soon after diagnosis

Conclusions: routine chemotherapy not recommended if patient does not have high-risk features; high-risk patients considered to have equivalent of stage III disease; bottom line (for surgeons)  —  refer patient to oncologist

Chemotherapy for patient with metastatic colon cancer: disease curable; in Swedish study of 2,280 consecutive cases, 537 patients had isolated liver metastases; of those, only 21 went to surgery; in similar study conducted in United States, only 3% of patients with liver metastases had surgery; patient with metastases isolated to one or­gan should be considered surgical candidate; old data on adjuvant chemotherapy covered only 5-FU; other agents currently used; hepatic artery infusion no longer standard of care; should be used only in context of clinical trial

European Organization for Research on the Treatment of Cancer Intergroup Trial 40983: patients randomized to perioperative FOLFOX or surgery alone; 93% had 1 to 3 liver metastases; FOLFOX associated with trend toward longer progression-free survival, but did not reach statistical significance; questions about study design persist

Conclusions: neoadjuvant chemotherapy evaluates tumor sensitivity; chemosensitivity is prognostic factor; can convert »10% to 20% of unresectable cases to resectable; however, if tumor no longer visible on imaging studies after chemotherapy, resection still indicated, if possible (tumor may not be completely gone); chemotherapy-as­sociated steatohepatitis (CASH)  —  occurs in »50% of patients who undergo chemotherapy; increases risk for mortality associated with liver resection; higher risk for CASH with obesity and chemotherapy

Rectal Prolapse: What Are the Options?

Bard C. Cosman, MD, Professor of Clinical Surgery, University of California, San Diego, School of Medicine, and Chief, Halasz General Surgery Section, Veterans Affairs San Diego Healthcare System

Pelvic relaxation syndrome: pelvic floor dysfunction that progresses to rectal and anal intussusception through sphincters; most common manifestation stress urinary incontinence; levator hiatus usually enlarged; rectal pro­lapse should be viewed as both intussusception and hernia; physical examination shows concentric circles (radial folds suggest hemorrhoids)

Procidentia: rectal prolapse; usually seen in elderly and mentally ill; female-to-male ratio 5:1; premorbid bowel disturbances  —  chronic constipation; incontinence (intussusception associated with pudendal neuropathy); con­dition entirely surgical

Preoperative work-up: anal manometry  —  results often predictable; sphincter generally weak; patients usually have pudendal neuropathy, with weak anal squeeze and weak anal tone; can document with manometry or digital examination and history; pudendal nerve latency   —evaluates pudendal nerve conduction; typically abnormal in patients with rectal prolapse; rarely performed (does not yield additional information or change management); defecography  —  directly documents rectal prolapse; patient  defecates stool containing radiopaque marker into radiolucent toilet; prolapse requiring surgery probably detectible without defecography

Colonoscopy: looks for lead point (actual location of intussusception); usually between 8 cm and rectosigmoid junction; in rare patients, lead point can be large polyp or cancer); not visible in most patients, but colonoscopy useful because most of these patients bleeding and in high-risk age group for colon cancer (allows examination of entire colon); colonoscopy recommended as minimal effective work-up for rectal prolapse

Anatomic defects: unclear whether cause or result of prolapse; include deep rectovaginal or rectovesical pouch (probably result; analogous to hernia sac dragged down by prolapsed rectum); weak pelvic floor (probably both cause and effect); unfixed rectum (most common feature of rectal prolapse; possibly cause); extra-long mesorectum (probably result); redundant sigmoid (common in general population; unclear whether present in all prolapse pa­tients; especially common among people with chronic constipation; may be related to cause of rectal prolapse); weak anal sphincter (concomitant with pudendal neuropathy); plan operation according to anatomic defects

Operative principles: fix rectum to sacrum (rectopexy); reset any intussuscepting segments; close pelvic floor (pro­duces better functional results); no operation fulfills all principles perfectly, but “one or two come close”

Surgical options: most produce acceptable results in experienced hands; no single procedure superior; transabdominal rectopexy  —  former standard of care; resection  —  can be done with or without rectopexy; both may be performed laparo­scopically; perineal proctectomy (Altmeier procedure)  —recreation of prolapse, removal of portion of rectum, and suture of sigmoid colon to anus without visible incision; Delorme plication  —  used only for rectal prolapse; thought to produce less morbidity because abdominal cavity avoided; encirclement (Thiersch operations)  —  involves tightening anal sphinc­ter outlet; can be “relegated to history”

Choosing an operation: rectopexy fixes rectum; does not resect intussuscepting segment, and does not close pelvic floor; may be best way to manage rectal prolapse; rectopexy, resection, and levatorplasty (tightening pelvic floor from above) fixes rectum, resects intussusception, and closes pelvic floor; “intuitive gold standard” (achieves all surgical goals); perineal proctectomy plus levatorplasty resects intussusception and closes pelvic floor, but with­out fixation of rectum (except secondary to scarring); plication achieves partial rectal resection, but neither closes pelvic floor nor fixes rectum (except via scarring)

Recommendation: ideally, operation that does not let prolapse recur, does not lead to incontinence, constipation, or sexual dysfunction, and has low morbidity

Counseling patient: abdominal operations associated with less risk for recurrence; resection, rectopexy and levator­plasty associated with short-term recurrence of 5%, 10-yr recurrence rate of »10%; in study with 20-yr follow-up, recurrence rate 30%; perineal proctectomy consistently associated with recurrence rate of 15% to 16%, but morbidity lower than that associated with other procedures; plication also associated with 15% recurrence rate; counsel patient that, in good candidates for abdominal surgery, 5- to 10-yr recurrence 5% to 10%; 5-yr recurrence associated with proctectomy surgery »15% (10-yr recurrence unknown, but probably slightly higher); however, may be more attractive to elderly patient due to lower morbidity; functional results of operations unpredictable; may lead to incontinence and constipation (both treatable); difficult to estimate risk because study findings vary widely; recommendation  —counsel patient to repair prolapse, see whether constipation occurs, and treat accord­ingly; warn patients that they may continue to have symptoms (eg, incontinence) experienced before prolapse de­veloped

Interaction between prolapse repair and functional problems: incontinence and rectal prolapse part of pelvic relax­ation syndrome, so they occur in tandem; pudendal neuropathy part of rectal prolapse and predisposes patients to incontinence; intussuscepting rectum may provide continence; removing it may increase incontinence, but re­vealing underlying incontinence may be beneficial; constipation  —  if chronic, removing prolapse may not re­solve; total abdominal colectomy may be indicated for rare carefully selected patients; functional results still unpredictable; in controlled studies, rectopexy with resection associated with greater improvement in constipa­tion than rectopexy alone; resection improves functional result and recommended whenever safe; levatorplasty with perineal proctectomy decreases risk for incontinence over proctectomy alone without increased incidence of constipation; limited recommendations  —perform resection as well as rectopexy if performing abdominal proce­dure; if doing perineal surgery, perform levatorplasty as well as proctectomy; both known to help, even if func­tional outcome remains uncertain

Incarceration: most rectal prolapses freely reducible, but may become incarcerated if intussuscepting segment be­comes edematous and fixed in prolapsed position; options include reducing prolapse, then choosing operation, or operating without reduction

Reduction: deliquescent agents effective; 1 lb table sugar packed on semipermeable membrane pulls fluid out and may shrink intussuscepting segment sufficiently to reduce it; reducing strangulated segment not recom­mended; better to operate with segment prolapsed; when reduction impossible, best option perineal proctec­tomy; experience with procedure recommended; other perineal operations such as Delorme procedure not applicable if incarceration present

Conclusions: surgery only treatment for rectal prolapse; surgeons should have at least one abdominal and one peri­neal operation in their armamentarium; candidates for perineal procedure  —  elderly or high-risk patients; proctec­tomy most sensible choice; abdominal operation  —  younger or healthier patients; resection plus rectopexy procedure of choice (decreases risk for constipation); add levatorplasty whenever possible; easiest with perineal op­erations; always consider perineal proctectomy in cases of incarceration and strangulation (procedure of choice for high-risk patients)

Suggested Reading

Altomare DF et al: Long-term outcome of Altemeier’s procedure for rectal prolapse. Dis Colon Rectum 52:698, 2009; André T et al: Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer. N Engl J Med 350:2343, 2004; Demirel AH et al: Sugar application in reduction of incarcerated prolapsed rectum. Indian J Gastroenterol 26:196, 2007; Glasgow SC et al: Recurrence and quality of life following perineal proctectomy for rectal prolaspe. J Gastrointest Surg 12:1446, 2008; Hoel AT et al: Prolapse of the rectum, long-term results of surgical treatment. Int J Colorectal Dis 24:201, 2009; Marshall JL et al: Adjuvant therapy for stage II and III colon cancer: consensus report of the International Society of Gastrointestinal Oncology. Gastrointest Cancer Res 1:146, 2007; Nordlinger B et al: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 371:1007, 2008; Parès D et al: An alternative management for high-risk patients with rectal prolapse. Colorectal Dis 11:531, 2009; Swanson RS et al: The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 10:65, 2003; Tou S et al: Surgery for complete rectal prolapse in adults. Cochrane Database Syst Rev 4:CD001758, 2008; Uen YH et al: Prognostic significance of multiple molecular markers for pa­tients with stage II colorectal cancer undergoing curative resection. Ann Surg 246:1040, 2007.