Management of rectal neoplasia in hereditary colorectal cancer patients

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Management of rectal neoplasia in hereditary colorectal cancer patients Jean H Ashburn PII: DOI: Reference:

S1043-1489(18)30035-6 10.1053/j.scrs.2018.06.006 YSCRS 639

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Please cite this article as: Jean H Ashburn , Management of rectal neoplasia in hereditary colorectal cancer patients, The End-to-end Journal (2018), doi: 10.1053/j.scrs.2018.06.006

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Management of rectal neoplasia in hereditary colorectal cancer patients Jean H Ashburn, MD1 1

Department of Surgery, Wake Forest University Baptist Medical Center, 1

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Medical Center Blvd, Winston-Salem, NC, 27517

Address for Correspondence: Jean H Ashburn, MD, FACS FASCRS, Assistant

Professor of Surgery, Department of Surgery Medical Center Blvd Wake Forest

University Baptist Medical Center Winston-Salem, NC 27517 USA, Telephone:

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336 7160547, Fax: 336 7169758, Email: [email protected]

Abstract

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Determining the optimal treatment for rectal cancer is a complicated challenge on its own but requires even more careful consideration when it occurs in patients

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with a hereditary colorectal cancer syndrome. Ideally, these patients are identified early and followed closely to prevent cancer. If cancer does arise, the standardized

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strategy for rectal cancer treatment used for the general population must be

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tailored to address the concerns of risk for metachronous neoplasia and functional outcomes that are unique to these patients. The best surgical approach considers

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both the primary cancer as well as the remaining unstable colorectum, and thoughtful timing of multimodal therapies helps to avoid negative effects on bowel reconstruction to maintain quality of life.

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Keywords rectal neoplasia, familial adenomatous polyposis, Lynch syndrome, hereditary colorectal cancer, ileoanal pouch

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Introduction

Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer death for both men and women in the United States.1 Rectal

cancer accounts for nearly 30% of these cases.2 Although less common than colon

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cancer, rectal cancer treatment is particularly challenging as it routinely makes use of multidisciplinary treatment modalities and employs intricate surgical technique for sphincter salvage and preservation of bowel function.

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Most CRC is sporadic and occurs secondary to the interplay between environmental factors and genetic predisposition. However, approximately 5% of

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CRC occurs in the background of hereditary CRC syndromes that predispose patients to develop neoplasia of the colorectum.3 Rectal cancer in patients with

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Lynch syndrome (LS) and familial adenomatous polyposis (FAP), the two most

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common heritable syndromes, poses distinct dilemmas as compared to that in the general population. These syndromes may affect both patient and family members

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alike. Therefore, aggressive treatment and surveillance strategies must be implemented to adequately address the primary malignancy and reduce the risk of additional non-colorectal, syndrome-associated malignancies.4 Ultimately, treatment options must be patient-centered with clear goals of treating the primary

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cancer, mitigating the increased risk for future cancer development, and preserving quality of life (QOL). This section will address the challenges of rectal cancer treatment in patients with heritable syndromes of LS and FAP and outline surgical strategies

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for treatment. Familial Adenomatous Polyposis

FAP is an autosomal dominant syndrome caused by an inherited germline mutation in the APC gene on chromosome 5q21.5,6 In the colorectum, this

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manifests as hundreds to thousands of colorectal adenomas and nearly 100%

colorectal cancer development.7 It affects both genders and all races equally.8 The syndrome has a nearly 100% penetrance, with 95% of patients exhibiting

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polyposis by age 35 years and, without surgery, CRC is inevitable.9 CRC is the most common cause of death in FAP patients, but FAP only accounts for 1% of

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all cases of CRC. There is a paucity of data related to the incidence of index rectal malignancy in these patients, as more attention has been placed on rectal cancer

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arising after prophylactic colon surgery is performed.

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The three general options for prophylactic surgical management of FAP are colectomy with ileorectal anastomosis (IRA), total proctocolectomy with end

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ileostomy (TPC-EI), and restorative proctocolectomy with ileoanal pouch (RPIPAA). Each option has unique oncologic and functional implications. Although TPC-EI is the best oncologic option for FAP patients who are accepting of a permanent ileostomy, patients desiring maintenance of intestinal continuity have the remaining two options: IRA or RP-IPAA. The decision to perform IRA or RP-

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IPAA is based on both the severity and distribution of polyposis. Patients with ‘rectal-sparing’ polyposis may be considered for IRA, a desirable option over RPIPAA due to the superior functional result in the majority of individuals. However, patients must undergo preoperative colonoscopy to remove all large

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polyps at risk for malignant development, and must be counseled regarding the importance of postoperative surveillance to reduce risk of subsequent cancer

developing in the remaining rectum. With IRA, patients experience better bowel

function, faster recovery, and lower risk for desmoid disease without the need for

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routine covering ileostomy.

Rates of rectal cancer after IRA have been reported as high as 59% after 23 years, with risk being dependent on a series of factors including number of

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rectal polyps, age, polyp size, presence of cancer in colon specimen, and compliance with rectal surveillance.10,11 Since rectal cancer risk is strongly related

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to rectal polyp burden, examining the rectum is a good starting point and can facilitate the decision to proceed with IRA. Church et al reported that patients

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who underwent IRA with ≤ 5 rectal adenomas and ≤ 1,000 colonic polyps did not

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require a subsequent proctectomy. Fifteen percent of patients with 6 to 20 rectal adenomas needed later proctectomy, but when ≥ 20 rectal adenomas were found,

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the incidence of subsequent proctectomy increased to >50%. Recently this principle has been adapted in favor of a conservative approach.12,13 Regardless of polyp burden, post-IRA surveillance is critical, mandating that all patients who elect to undergo IRA should understand the need for ongoing endoscopy. A study from the Finnish Cancer Registry showed a rate of proctectomy after IRA for

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FAP to be 28%. Overall polyp burden prior to IRA was not reported, but those with attenuated FAP did not require proctectomy. The majority of those who underwent completion proctectomy after IRA did so for either a rectal cancer or uncontrollable polyp burden, underscoring the critical role for surveillance after

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surgery.14

Patients who desire complete removal of the at-risk colorectum but wish to maintain intestinal continuity are evaluated for RP-IPAA. This approach

requires deep pelvic dissection to remove the rectum and create an ileal pouch

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which brings about different and sometimes more difficult postoperative

challenges than those with IRA. Deep pelvic surgery carries risk for sexual and/or urinary dysfunction, and may promote both scar formation and development of

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desmoid disease in the pelvis, both undesirable side effects with implications on fertility, QOL, and fate of the ileal pouch.15-17 With good results, patients after

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RP-IPAA experience 5-6 daily bowel movements with good control and are able to defer pouch emptying for at least one hour.

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If RP-IPAA is performed, one must choose between a stapled or hand-

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sewn pouch-anal anastomosis, with the latter being routinely performed with mucosectomy. Proponents of a stapled anastomosis report that it is a simpler

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approach, has better function, is easier to survey, and is associated with fewer complications.18 Opponents highlight the risk for development of neoplasia in the rectal cuff or anal transition zone (ATZ), which is reported to be twice that of mucosectomy with handsewn IPAA.19 If neoplasia does develop in the ATZ, one can perform pouch advancement with excision of the ATZ to deal with neoplasia

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if the ATZ is relatively short (<2cm). This procedure is more technically difficult if a lengthier ATZ (>2cm) is left in place, and transanal/transabdominal IPAA revision may be necessary to deal with a pathologic ATZ, as cancer can develop here (Figure 1).20 Patients with handsewn IPAA are more likely to experience

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anal seepage and anoperineal irritation, particularly at night, as well as

anastomotic stenosis. It also does not reduce the risk for cancer to nil as islands of mucosa can remain and harbor neoplasia.18,19 All pouches, regardless of surgical approach, must be surveyed on an annual basis.20

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Another dilemma is the approach to neoadjuvant chemoradiotherapy

(NAT) in the FAP patient with rectal cancer who desires RP-IPAA. Although the components of multimodal therapy for rectal cancer in these patients do not differ

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from sporadic rectal cancers, the timing and arrangement of treatments may be differently considered. NAT is standard for most locally advanced rectal cancer,

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and is typically administered prior to surgery due to a perceived greater effect, better patient compliance and improved local recurrence rates and survival.21-23 If

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a pelvic pouch is the desired surgical outcome, chemoradiotherapy must be given

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only in the preoperative time period because radiating an IPAA can have significant detrimental effects on pouch function.24 Because of this concern, every

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hereditary CRC patient undergoing prophylactic surgery that involves pelvic reconstruction must be closely evaluated for a hidden rectal cancer with imaging and endoscopy, and even apparently early cancers must undergo stringent local staging to make certain that radiation therapy is not needed.

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Despite meticulous preoperative investigation, the clinician may still face an intraoperative or postoperative finding of rectal cancer that was not identified preoperatively. In this case, it is advantageous to choose one of the following strategies to treat cancer and preserve bowel function: resect cancer and restore

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continuity with IPAA, omitting any radiation therapy; terminate the operation

prior to resection and initiate NAT or; resect the cancer and create an ileostomy allowing for return to the OR and IPAA creation after radiation therapy is complete (or keep the permanent ileostomy).

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Every effort must be made to avoid radiating a pelvic pouch, which is a

setup for pouch failure and poor QOL (Figure 2).25 Preoperative radiation therapy prior to pouch creation may also negatively affect functional outcomes. A recent

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study of 56 patients who underwent IPAA creation after pelvic radiation for colitis-associated cancer showed a strong association between preoperative pelvic

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radiation and the risk for pouch failure by Kaplan-Meier analysis.26 Even though these were not heritable rectal cancers, the potential impact of NAT on

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postoperative IPAA function should be considered and patients counseled

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accordingly.

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Lynch Syndrome LS, the most common syndrome of dominantly inherited colorectal

cancer, is defined as the presence of a germline mutation in the DNA-mismatch repair (MMR) gene system that results in microsatellite instability and loss of function.27-29 Affected patients carry an increased risk of developing both CRC

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and extracolonic malignancies at a young age. Because these germline MMR mutations are dominantly inherited, a strong family history of early-onset cancer is often apparent. LS differs from hereditary nonpolyposis colorectal cancer (HNPCC) in that HNPCC is defined as a family who meets Amsterdam criteria,

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clinical criteria that leads to overlap with LS, a term reserved for those with the MMR gene mutation regardless of family history. In general, the treatment recommendations here apply to both LS and HNPCC.

The incidence of CRC in patients with LS is 50-80%, a nearly 6-fold

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increased risk compared with the general population.30,31 Although prophylactic colectomy is not routinely recommended for patients without colonic neoplasia, surgery is performed once a patient develops adenocarcinoma or carries a polyp

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burden not well-controlled with endoscopic measures. Colon resection can be considered both prophylactic and therapeutic in LS since the primary cancer is

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resected along with other at-risk colorectal mucosa. The recommended extent of resection is debated. Patients may undergo a standard segmental colorectal

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resection, similar to that performed for a sporadic cancer, or an extended

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colectomy with IRA to prevent a metachronous colon cancer, reported to occur at a rate of 15-25% at 10 years, and estimated to be 62% at 30 years.32-35

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Although most CRC in LS is proximal to the splenic flexure, rectal cancer

is surprisingly common and may occur in up to 30% of patients as an index malignancy.27,36 Surgical decision-making is complicated and must consider characteristics of the index rectal cancer, patient age and comorbidities and risk for metachronous malignancy. Patients who are suspected to have LS should

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undergo genetic testing and counseling prior to making a final decision on extent of surgical resection, if possible. This is a critical step even when patients are anxious to initiate treatment. Standard staging of the rectal cancer is necessary, with pelvic imaging for local staging, cross-sectional imaging of the chest,

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abdomen and pelvis to rule out distant metastatic disease, lab studies including

carcinoembryonic antigen, and complete colonoscopy if not already performed to rule out any synchronous lesions.

Patients may be surgically treated with proctosigmoidectomy with

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reconstruction (colorectal or coloanal anastomosis), abdominoperineal excision of the rectum (APER), or total proctocolectomy with or without restoration of intestinal continuity (TPC-EI, RC-IPAA). Each decision is patient-specific and

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takes into consideration the stage of the tumor and its relation to the sphincter complex, risk for metachronous disease, surgeon ability, functional goals, and

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fitness of the patient. Rectal resection is performed as a therapeutic maneuver, but whether to extend the resection to include a complete proctocolectomy is debated.

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Anterior proctosigmoidectomy offers more favorable bowel function, as the

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majority of the colon is preserved. However, this approach leaves more surface area at risk for development of metachronous cancers and requires both patient

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and clinician compliance to undergo thorough annual surveillance. Since the entire colorectal mucosa is considered oncologically unstable, total proctocolectomy allows for therapeutic cancer resection and prophylactic removal of at risk mucosa. This strategy is similar to complete colectomy with IRA for LS-associated colon cancer. The surgeon may offer restoration of intestinal

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continuity with IPAA if tumor stage/location and patient factors allow and if sphincter function is favorable. While the risk for metachronous colon cancer after proctectomy for rectal cancer may be less than that following a colon cancer resection in the setting of

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LS, it is still a clinically significant risk. One study from Roswell Park Cancer Institute reported that 18% patients who met Amsterdam criteria or had a

germline MMR mutation and underwent proctectomy for rectal cancer developed a metachronous cancer at a median 203 month follow up.27 Another retrospective

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study from Germany reported that 54% (6/11) of patients with HNPCC developed metachronous colon cancer after proctectomy (median follow-up 7.4 years).36 More recently, a study by Kalady et al reported on 33 HNPCC patients with a

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primary diagnosis of rectal cancer treated by proctectomy. Five patients (15.2%) developed metachronous adenocarcinoma, and 13 patients developed high-risk

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adenomas at a median of 6 years (range 3.5-16) after proctectomy. Together, 17 of 33 patients (51.5%) developed high-risk adenoma or cancer after

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proctectomy.37

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Ultimately, surgical treatment in the setting of rectal cancer in LS must be individualized. Proctocolectomy with or without IPAA should be considered in

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patients fit for surgery because of the substantial risks for metachronous neoplasia after proctectomy alone. Patients unable to tolerate the morbidity and worse functional outcomes associated with a more extensive resection require segmental resection with close surveillance with annual endoscopic evaluation of the remaining at-risk mucosa.37-39

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Other complicated decisions to make when treating rectal cancer in LS relate to the use of chemoradiotherapy for locally advanced rectal cancer, and the likelihood of future metastatic disease based on tumor features. As previously discussed, preoperative neoadjuvant treatment with radiation is preferred prior to

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pouch formation since radiation to an ileal pouch is associated with increased

rates of pouch failure. For select patients with stage III and stage IV rectal cancer, the risk of future progressive metastatic disease outweighs the potential

prophylactic benefit achieved with a completion colectomy done at the time of

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proctectomy for the primary cancer. If patients are likely to succumb to

metastatic disease, there is no utility in preventing a future metachronous cancer with total proctocolectomy. Thus, in these patients, a less invasive operation with

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colonic preservation is the preferred treatment approach, if an operation is to be performed at all.38 Chemoradiotherapy is commonly used for locally advanced

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rectal cancers in LS, and evaluation for multi-modal therapy should be conducted similar to that for new sporadic rectal cancer patients. As discussed in previous

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sections, radiating a colonic or ileal pouch created for intestinal reconstruction can

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result in disastrous function and should be avoided if at all possible.24-26

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Conclusion

The treatment of rectal neoplasia in patients with LS and FAP is a

multidisciplinary clinical task with unique challenges compared to the sporadic rectal cancer population. Aggressive surgical management mitigates risk for

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metachronous neoplasia, but should be balanced with thoughtful consideration of

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bowel function and QOL.

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Figure Legends

Figure 1: Anal transition zone adenocarcinoma in a resected ileal pouch anal anastomosis (printed with permission, Dr Feza Remzi)

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Figure 2: A contracted, fibrotic ileal pouch anal anastomosis excised due to failure after pelvic radiation