Treatment of small bowel neoplasms

INTRODUCTION — A variety of tumors, both malignant and benign, arise within the small intestine. Malignant tumors include adenocarcinomas, neuroendocrine (carcinoid) tumors, sarcomas, and lymphomas, while benign lesions include adenomas, leiomyomas, lipomas, and hamartomas.

The treatment of the various types of neoplasms that arise in the small bowel will be reviewed here. The epidemiology, clinical manifestations, diagnosis, and staging of small bowel tumors are discussed separately. (See "Epidemiology, clinical features, and types of small bowel neoplasms" and "Diagnosis and staging of small bowel neoplasms".)

ADENOCARCINOMA

Locoregional disease

Surgery — Localized invasive adenocarcinomas of the small bowel are best managed with wide segmental surgical resection. Resection of the primary and investing mesentery achieves surgical clearance of both the primary and the regional nodes at risk for metastases, and provides important staging information that impacts decisions regarding the need for adjuvant therapy (see below). However, resection of adequate mesentery may be limited by the proximity of the nodes or tumor to the superior mesenteric artery. The optimal number of regional lymph nodes needed for adequate staging is debated [1-4], but guidelines from the National Comprehensive Cancer Network (NCCN) recommend that a goal for all small bowel adenocarcinoma resections should be the retrieval of at least eight regional nodes [5].

Duodenal tumors — Pancreaticoduodenectomy is required for tumors involving the second portion of the duodenum and for those invading into any portion of the ampulla or pancreas. For tumors involving the first, third, and fourth portions of the duodenum, there is debate regarding the need for pancreaticoduodenectomy compared with wide local excision. Those favoring pancreaticoduodenectomy note the more radical clearance of the tumor bed and regional lymph nodes [6-8]. However, the majority of data, though limited by sample size, demonstrate similar outcomes between pancreaticoduodenectomy and wide local excision:

●Unlike pancreatic cancers, which diffusely infiltrate into the surrounding soft tissues, the extension of duodenal adenocarcinomas into adjacent tissues is usually a more localized process, and tumor-free resection margins may be obtained without resection of adjacent organs and soft tissues. Because a negative margin is critical to a curative procedure, the margin status of the resected specimen must be confirmed on frozen-section and subsequent permanent histologic sections [6,9,10].

●A number of retrospective studies have not shown a survival benefit for pancreaticoduodenectomy as compared with segmental resection [11-16]. The largest series, from the Mayo Clinic, analyzed 68 patients with duodenal adenocarcinoma; 50 underwent radical surgery (pancreaticoduodenectomy or total pancreatectomy) while 18 had limited surgery (segmental duodenal resection or transduodenal excision) [17]. There was no significant difference between the two groups in terms of five-year overall survival (52 percent versus 61 percent), rate of margin-negative resections, or local recurrence rates.

●In an analysis of 1161 cases of small bowel adenocarcinoma derived from the Surveillance, Epidemiology, and End Results (SEER) database, the outcomes of 865 patients undergoing radical resection were compared with those of 746 who had simple resection [18]. Radical resection was not associated with improved disease-specific or overall survival, even when the analysis was controlled for confounding factors such as more poorly differentiated and larger tumors, but also a larger number of retrieved lymph nodes in the radical resection group.

These observations support the view that segmental resection provides an equivalent survival benefit to that of a more extensive resection for lesions in the distal third or fourth portions of the duodenum, and satisfies the principle of en bloc resection without the morbidity of a pancreaticoduodenectomy. As long as a margin-negative resection can be obtained, segmental resection is preferred over pancreaticoduodenectomy for tumors arising in the third and fourth portions of the duodenum to the left of the superior mesenteric artery.

For noninvasive in situ (Tis, (table 1)) lesions, endoscopic resection is a reasonable option. T1 lesions may be considered for endoscopic resection, though the exact rate of recurrence has not been well defined, and support for this approach is based upon only a small single institution retrospective series [19].

Jejunoileal tumors — Adenocarcinomas involving the jejunum or proximal ileum should be treated by wide excision of the malignancy and surrounding tissues at risk for contiguous spread. Tumors of the distal ileum require resection of the ileocolic artery and associated regional lymph nodes.

Outcomes — At the time of diagnosis, between 65 and 76 percent of patients with a small bowel adenocarcinoma are without distant metastases and potentially resectable; approximately one-half of these have regional nodal involvement [20,21]. In general, five-year survival rates for small bowel adenocarcinoma are worse than for similarly staged colon cancers, particularly for node-positive disease [1,22-24]. Nodal involvement is one of the strongest predictors of long-term survival [1,2,16,22,25-27]. In a systematic review, five-year overall survival rates for individuals with node-positive and node-negative disease were 21 versus 65 percent [16].

Five-year disease-specific survival by stage (table 1) [28] for 4995 cases of small bowel adenocarcinoma reported to the National Cancer Database (NCDB) between 1985 and 1995 were as follows [22]:

●Stage I – 65 percent

●Stage II – 48 percent

●Stage III – 35 percent

●Stage IV – 4 percent

However, in a Surveillance, Epidemiology, and End Results (SEER) registry analysis of 1991 cases with stage I, II, or III disease from 1988 to 2005, five-year disease-specific survival was higher: stage I, 85 percent; stage II, 69 percent; and stage III, 50 percent [2]. In addition, this analysis showed that the number of lymph nodes evaluated was a strong prognostic factor with markedly improved five-year disease-specific survival in patients with ≥8 lymph nodes evaluated: stage I, 95 percent; stage II, 83 percent; and stage III, 56 percent. These data, in conjunction with those from two additional studies evaluating the SEER registry, suggest that a portion of stage I or II small bowel adenocarcinomas are undergoing inadequate lymph node evaluation, and consequently being understaged (and undertreated) [2,3,29]. This appears to be particularly true for duodenal adenocarcinomas; in one study, the assessment of eight or more lymph nodes resulted in an improvement in disease-specific survival of 33 and 50 percent for patients with stage I and II disease, respectively [1].

Site also impacts prognosis. Five-year disease-specific survival rates are worse for duodenal primaries than for tumors arising in the jejunum or ileum in most [2,21,22,29-32] but not all [20,24,33] series.

Besides tumor site, and the presence of nodal and distant metastases, other poor prognostic factors include positive resection margins, lymphovascular involvement, T4 tumor stage, extent of nodal disease, and poorly differentiated histology [2,9,10,20-22,25,31,33-38]. Positive resection margins increase the rate of local failure, while lymph node involvement and transmural invasion of the bowel wall correlate with distant failure [15,17].

Adjuvant therapy — Optimal perioperative therapy is not defined. We prefer that eligible patients with resected stage I to III small bowel adenocarcinoma be enrolled in clinical trials testing the benefit of adjuvant therapy, if possible. One such trial, the BALLAD trial, is recruiting internationally, and a similar trial is underway in Japan [39].

If a clinical trial is not available or participation is not feasible, we suggest adjuvant chemotherapy for all patients with lymph node-positive, completely resected small bowel adenocarcinomas, in part extrapolating from published data in resected node-positive colon cancer, where routine use of adjuvant chemotherapy significantly improves survival. As with node-positive colon cancer, we suggest use of an oxaliplatin-based regimen. Options include:

●Capecitabine plus oxaliplatin (table 2), largely based upon its activity in metastatic small bowel adenocarcinoma. (See 'Systemic therapy' below.)

●Oxaliplatin plus short-term infusional fluorouracil (FU) and leucovorin (ie, FOLFOX (table 3)), extrapolating from benefit in patients with node-positive colon cancer. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer".)

For those with completely resected T3 or T4 node-negative resected small bowel adenocarcinomas, observation or six months of adjuvant chemotherapy are both acceptable options, and we base our decision-making on clinicopathologic features, molecular prognostic factors such as deficient mismatch repair (dMMR), and patient preference, taking the following issues into account:

●Patients with high-risk features (eg, T4 primary, few lymph nodes examined, tumor perforation) could be offered adjuvant chemotherapy, although as with stage II colon cancer, there is no evidence that these features predict for responsiveness to adjuvant therapy. (See "Adjuvant therapy for resected stage II colon cancer", section on 'Clinicopathologic features'.)

●Extrapolating data from colon cancer, patients whose tumors have dMMR may have a better outcome than those with proficient mismatch repair, and guidelines from the NCCN use this feature to recommend observation alone after resection of a T3 or T4 node-negative small bowel adenocarcinoma [5]. If adjuvant chemotherapy is chosen in this setting, an oxaliplatin-containing regimen should be used, and not just a fluoropyrimidine. (See "Adjuvant therapy for resected stage II colon cancer", section on 'Prevalence of MMR enzyme deficiency'.)

If adjuvant chemotherapy is chosen for node-negative disease, we suggest a fluoropyrimidine alone (capecitabine, leucovorin-modulated FU), as long as the tumor has proficient mismatch repair. In the setting of dMMR, an oxaliplatin-containing regimen would be chosen rather than a fluoropyrimidine alone. (See "Adjuvant therapy for resected stage II colon cancer", section on 'Should an oxaliplatin-containing regimen be used?' and "Adjuvant therapy for resected stage II colon cancer", section on 'High-risk tumors and benefit of oxaliplatin'.)

Given the higher risk of local failure for patients with node-positive duodenal adenocarcinomas [15,34,40] and those with a positive resection margin, the addition of fluoropyrimidine-based chemoradiotherapy to a course of systemic oxaliplatin-based chemotherapy is reasonable in these situations, although whether this improves survival is not established. (See 'Chemoradiotherapy for duodenal primaries' below.)

Importantly, for complete staging, all patients should undergo contrast-enhanced computed tomography (CT) of the abdomen/pelvis and chest prior to initiation of adjuvant therapy.

Rationale — There is a paucity of data addressing the benefit of adjuvant therapy (chemotherapy, radiation therapy [RT], or both) after resection of small bowel adenocarcinomas, and its role remains undefined. A year 2018 meta-analysis of six observational studies (totaling approximately 400 patients) concluded that there was no survival benefit for adjuvant therapy after curative resection, albeit with very wide confidence intervals (odds ratio 1.14, 95% CI 0.60-2.15) [16].

The rationale for use of systemic adjuvant therapy in small bowel adenocarcinoma is based on both the known patterns of recurrence for this disease and an extrapolation from data demonstrating a significant survival benefit in patients with node-positive colon cancer (see "Adjuvant therapy for resected stage III (node-positive) colon cancer"):

●Among patients with completely resected small bowel adenocarcinoma, failure patterns are primarily systemic rather than local [17,20,37,41]. In a representative series of 146 patients undergoing potentially curative resection of a small bowel adenocarcinoma, 56 relapsed at a median time of 25 months, and the patterns of relapse were distant (n = 33), peritoneal carcinomatosis (n = 11), abdominal wall (n = 4), and local recurrence (n = 10) [20].

●One exception to this general rule is duodenal adenocarcinomas, where local failure rates as high as 41 to 50 percent are reported after surgical resection alone [15,17,27,34,40]. This provides the rational for considering chemoradiotherapy in this setting.

Benefit of chemotherapy — There are no prospective trials testing any adjuvant therapy strategy in small bowel adenocarcinoma, and the retrospective analyses that have addressed the issue have uniformly failed to suggest any overall survival benefit from any adjuvant approach [6,17,20,24,27,33,34,40,42,43]. However, treatment bias may have influenced the result. In most of these reports, the patients who were chosen for adjuvant therapy were those believed to have the highest risk of recurrence (and therefore, a worse prognosis) with surgery alone.

To control for potential treatment bias, investigators conducted a propensity score-matched analysis using data on 4746 patients with resected small bowel adenocarcinoma reported to the NCDB between 1998 and 2011 [44]. Cox regression was used to identify the covariates of overall survival, and propensity scores were developed that accounted for all factors significantly associated with either the receipt of adjuvant chemotherapy or the survival hazard from Cox modeling. In the propensity score-matched cohort of subjects receiving adjuvant chemotherapy (n = 1142) or surgery alone (n = 1155), there was a significant survival advantage for adjuvant chemotherapy versus surgery alone (median survival 63 versus 45 months, p <0.001). When stratified by pathologic stage, there was a significant survival benefit for adjuvant chemotherapy for those patients with resected stage III (node-positive) disease (median 42 versus 26 months, three-year actuarial survival 55 versus 41 percent). This benefit was observed for tumor located both in the duodenum (median overall survival 34 versus 24 months, p = 0.002) and in the jejunum/ileum (median overall survival 53 versus 30 months, p = 0.003). There was only a trend toward a survival benefit for stage I and II disease, regardless of tumor location. Although suggestive of a benefit from adjuvant chemotherapy, this is not a definitive study. Propensity analysis is limited by the availability in the database of all of the variables that might impact outcomes.

Despite the lack of data from randomized trials supporting a benefit from adjuvant therapy, data from a nationwide survey, registry-based series from the NCDB, and a population-based French registry series reveal an increase in the use of adjuvant chemotherapy for regionally advanced small bowel adenocarcinoma over the last 30 years [21,22,44,45].

Chemoradiotherapy for duodenal primaries — As noted above, patients with duodenal cancer have a higher local failure rate after surgical resection alone. Separate reports have focused on the role of adjuvant chemoradiotherapy after complete resection of a duodenal adenocarcinoma:

●A retrospective study from the Mayo Clinic included 68 patients who had curative resection of duodenal adenocarcinoma [17]. Twenty-five recurred, 21 with distant disease. Seventeen patients received adjuvant chemoradiotherapy with concurrent FU after complete resection, but there was no significant advantage in terms of survival or cancer recurrence.

●A similar lack of benefit for adjuvant chemoradiotherapy was noted in a multi-institutional retrospective series of 122 patients with duodenal adenocarcinoma; adjuvant chemoradiotherapy was administered to 34, and the five-year survival was no better than that of the remaining patients who did not receive it (47 versus 48 percent) [40].

●A report from Duke University compared outcomes among 16 patients treated with surgery alone with those among 16 nonrandomly assigned patients treated with either postoperative or preoperative FU-based chemoradiotherapy (50.4 Gy) in addition to surgery [34]. Adjuvant chemoradiotherapy did not significantly improve five-year overall survival (57 versus 44 percent, p = 0.42), although there was a trend favoring treatment in those who underwent a complete (R0) resection (five-year survival 83 versus 53 percent, p = 0.07), and local failure rates were lower (31 versus 44 percent).

As with prior retrospective reports, treatment bias may have influenced these results. Furthermore, the independent contribution of RT in patients receiving adjuvant chemotherapy has not been established. This issue was evaluated in a propensity score-matched analysis of 1028 patients with surgically resected duodenal adenocarcinoma who received adjuvant therapy, derived from the NCDB between 1998 and 2012 [43]. The addition of RT to adjuvant chemotherapy did not significantly improve survival, even in high-risk patients (ie, node-positive, T4 primary tumors, inadequate lymph node staging, poorly differentiated histology, or margin-positive resections).

Indications for neoadjuvant therapy — Although neoadjuvant chemotherapy and/or chemoradiotherapy has only been studied in a very small number of patients, this approach is promising [34,46-48]. In the largest report of 32 patients with localized duodenal adenocarcinoma, 2 of 11 patients treated with preoperative RT and concurrent FU-based chemotherapy had a pathologic complete response [34]. All were subsequently resected, and none of the 11 had involved lymph nodes at the time of resection.

There are no widely accepted criteria for selecting patients for a neoadjuvant approach. Guidelines from the NCCN suggest initial oxaliplatin-containing chemotherapy (FOLFOX (table 3), or CAPOX (table 2) or FOLFOXIRI (table 4)), possibly followed by chemoradiotherapy (for a duodenal primary) in patients with locally unresectable disease and for those who are medically inoperable, followed by reevaluation for conversion to resectable disease [5]. We consider the use of neoadjuvant chemotherapy on a case-by-case basis, mainly in patients with bulky or locally advanced categorically unresectable disease.

Metastatic disease

Systemic therapy

Conventional cytotoxic therapy — For patients who are able to tolerate it, we suggest systemic chemotherapy rather than supportive care alone. We use an oxaliplatin-based chemotherapy regimen as a first-line regimen.

In the absence of randomized trials comparing different chemotherapy regimens, the majority of phase II and retrospective data support a fluoropyrimidine plus a platinum-type drug for first-line chemotherapy in patients with advanced small bowel adenocarcinoma. We prefer the CAPOX (table 5) or mFOLFOX6 (table 3) regimens, or if a patient is not an appropriate candidate for intensive therapy, a fluoropyrimidine alone (capecitabine or leucovorin-modulated FU). The NCCN guidelines recommend oxaliplatin plus irinotecan and leucovorin-modulated FU (FOLFOXIRI) as an option and this is a reasonable alternative, though no data in small bowel adenocarcinoma exist, and this recommendation is based upon extrapolation from the treatment of colorectal cancer. The use of treatments targeting vascular endothelial growth factor (VEGF, eg, bevacizumab) is controversial as there are no data from randomized trials demonstrating the benefit of adding bevacizumab to a backbone cytotoxic regimen in advanced small bowel adenocarcinoma.

In general, systemic chemotherapy for patients with advanced small bowel adenocarcinoma has been based on treatment principles established for metastatic colorectal cancer. (See "Systemic therapy for metastatic colorectal cancer: General principles" and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach" and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy".)

Although randomized trials have not been undertaken, a number of retrospective series suggest that patients with metastatic or locally advanced unresectable small bowel adenocarcinoma who get chemotherapy live longer than do those who do not receive chemotherapy (table 6) [20,33,49-51]. However, since it is likely that chemotherapy was offered to healthier patients with more indolent disease biology, selection bias likely accounts for at least some of these findings.

The majority of published reports evaluating chemotherapy for small bowel adenocarcinoma are retrospective in nature. Relatively few prospective phase II studies have been reported:

●In a single-institution study, the CAPOX regimen (capecitabine 750 mg/m² twice daily on days 1 through 14, and oxaliplatin 130 mg/m² on day 1, every 21 days) was administered to 31 patients with advanced, unresectable or metastatic small bowel or ampullary adenocarcinoma [52]. Among the 25 patients with metastatic disease, the response rate was 52 percent (with three complete responses) and median overall survival was 15.5 months. The response rate in the subgroup of 18 patients with small bowel adenocarcinoma was 61 versus 33 percent with ampullary adenocarcinoma.

The optimum dose of capecitabine for use in the CAPOX regimen is debated. However, based on the above trial, we suggest use of 750 mg/m² twice daily on days 1 through 14 of each 21-day cycle (table 2), rather than the 850 mg/m² dose as is commonly used for treatment of colorectal cancer.

●Encouraging results were also seen with CAPOX or the modified FOLFOX6 regimen (table 3) in a multicenter phase II trial of 24 patients with locally unresectable or metastatic small bowel adenocarcinoma [53]. The objective response and disease control rates were 32.3 and 61.7 percent, respectively, and median duration of progression-free and overall survival were 6.3 and 14.2 months, respectively.

A second multicenter phase II trial of 33 patients using a modified FOLFOX regimen (FU 2600 mg/m² continuous infusion over 46 hours starting day 1, oxaliplatin 85 mg/m² on day 1, leucovorin 400 mg/m² day 1, every 14 days) demonstrated an objective response rate of 49 percent, median TTP of 7.8 months, and median OS of 15.2 months [54].

●The addition of irinotecan to a fluoropyrimidine and oxaliplatin combination demonstrated similar activity [55]. Among 28 patients with advanced small bowel adenocarcinoma receiving UGT1A1 genotype-selected dosing of irinotecan, oxaliplatin, and capecitabine, the objective response rate was 57 percent and median progression-free survival (PFS) and overall survival were 8.7 and 12.7 months. UGT1A1 genotype dosing of these chemotherapy agents is not a standard widely accepted practice. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'UGT1A1 polymorphisms'.)

●A potential role for taxanes was suggested in a phase II study of nanoparticle albumin-bound paclitaxel (nabpaclitaxel); 2 of the 10 enrolled patients with small bowel adenocarcinoma had an objective response [56].

The efficacy of other regimens for the treatment of small bowel adenocarcinoma has been examined in retrospective case series [49-52,57-65]. The following represents the range of findings:

●One series included 80 patients with metastatic small bowel adenocarcinoma treated at MD Anderson between 1978 and 2005 with a variety of chemotherapy regimens [58]. Twenty-nine patients received FU with a platinum (19 cisplatin, four carboplatin, six oxaliplatin), 41 received FU-based therapy without a platinum (FU alone in 32, FAM or FU and mitomycin in six, and other FU combinations in three), and 10 received non-platinum and non-FU-based therapy.

Compared with other regimens, FU combined with a platinum drug was associated with significantly higher objective response rates (46 percent versus 16 percent with all others) and median PFS (8.7 versus 3.9 months), but median overall survival was comparable (14.8 versus 12 months).

●Another report included 93 patients with advanced small bowel adenocarcinoma (86 percent metastatic) who were treated with leucovorin-modulated FU, FOLFOX (oxaliplatin plus leucovorin and short-term infusional FU), FOLFIRI (irinotecan plus leucovorin and short-term infusional FU), or FU plus leucovorin and cisplatin [65]. Although this was not a randomized trial, response rates were highest with FOLFOX (13 of 38 partial responses, 34 percent), and median overall survival was also highest in the patients treated with FOLFOX (17.8 months).

An apparent survival advantage for fluoropyrimidine/oxaliplatin combination therapy over other regimens in the setting of advanced small bowel adenocarcinoma has also been shown by others [66].

●Irinotecan and gemcitabine are also active agents [49,50,59,60,63,64,67]. As examples:

•In the series of 44 patients undergoing palliative therapy for advanced disease described above, 5 of the 12 patients receiving irinotecan-based therapy (six FOLFIRI (table 7), two capecitabine plus irinotecan, and four single agent irinotecan) had a partial response (42 percent) [49]. Less impressive results have been reported with second-line FOLFIRI after failure of initial platinum-based chemotherapy (response rate 20 percent, median PFS 3.2 months) [67].

•The activity of first-line gemcitabine was addressed in the series of 44 patients undergoing palliative therapy for advanced disease described above [49]. Seven of 17 patients (41 percent) receiving a gemcitabine-based regimen (nine single-agent gemcitabine, four gemcitabine plus FU, four gemcitabine plus capecitabine) had an objective response.

Molecular profiling and targeted therapies — We recommend multigene panel-based somatic genomic testing for all metastatic small bowel adenocarcinomas, if the patient would be a candidate for targeted therapy.

Increasingly, biomarker expression is driving therapeutic decision making in patients with advanced refractory cancer. Small bowel adenocarcinomas have a different genomic profile compared with colorectal and gastric adenocarcinomas, including variations in the frequency and types of alterations of KRAS, APC, BRAF, ERBB2/HER2, and other genes, some of which may be potentially actionable targets for therapy [68-70]. Multigene panel-based somatic (tumoral) genomic testing has the potential to identify targetable alterations and patients for whom targeted therapies might be of benefit. In some cases, germline testing may also reveal potential treatment targets (eg, deficient mismatch repair as seen in Lynch syndrome). (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Germline mutation'.)

ASCO has issued a provisional clinical opinion that supports germline and somatic genomic testing in metastatic or advanced cancer when there are genomic biomarker-linked therapies approved by regulatory agencies for their cancer [71]. Given the tissue-agnostic approvals for any advanced refractory cancer with a high tumor mutational burden or DNA mismatch repair deficiency (checkpoint inhibitor immunotherapy), or neurotrophic tyrosine receptor kinase (NTRK) fusions (TRK inhibitors), or RET (rearranged in transfection) fusions (selpercatinib), this provides a rationale for testing for all solid tumors, if the individual would be a candidate for these treatments. Testing should also be considered to determine candidacy for targeted therapies approved for other diseases in patients without approved genomic biomarker-linked therapy; however off-label/off-study use of such therapies is not recommended when a clinical trial is available, or without evidence of meaningful efficacy in clinical trials. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Cancer screening and management' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors" and "TRK fusion-positive cancers and TRK inhibitor therapy".)

However, few data are available exploring the benefit of specific biologic or targeted therapies in advanced small bowel adenocarcinoma :

●Bevacizumab is a monoclonal antibody targeting VEGF. Bevacizumab (7.5 mg/kg every 21 days) was combined with CAPOX (capecitabine 750 mg/m² twice daily on days 1 through 14 and oxaliplatin 130 mg/m² on day 1 every 21 days) in a single-institution phase II study of 30 patients with advanced, unresectable or metastatic small bowel or ampullary adenocarcinoma [72]. Treatment was reasonably well tolerated, and the response rate was 48 percent, median PFS was 8.7 months, and median overall survival was 12.9 months. Whether these results are better than could be achieved with CAPOX will require a randomized trial.

●Limited data are available for the role of anti-epidermal growth factor receptor (EGFR) therapy. Among patients with advanced colorectal cancer, RAS mutations are associated with resistance to agents that target EGFR (see "Systemic therapy for metastatic colorectal cancer: General principles", section on 'RAS'). In addition, given more recent colorectal data suggesting that anti-EGFR therapy effectiveness relates to colon sidedness, the role of anti-EGFR therapy in small bowel adenocarcinoma, given its midgut derivation (right sidedness), is uncertain:

•Possible benefit for cetuximab, a monoclonal antibody targeting EGFR, was suggested in a report of four patients with advanced small bowel adenocarcinoma who received the drug in conjunction with irinotecan; two had previously failed an irinotecan-based combination regimen [73]. There were three objective responses, one of which was complete. Three of the four patients had wild-type K-ras tumors.

•An additional case report describes a minor response to single agent cetuximab in a patient with metastatic duodenal adenocarcinoma whose K-ras status was wild-type [74].

•On the other hand, benefit for single-agent panitumumab (a different anti-EGFR antibody) could not be shown in a small prospective study of eight patients with RAS wild-type small bowel adenocarcinoma [75].

●ERBB2 alterations occur in approximately 10 to 20 percent of small bowel adenocarcinoma, although alterations tend to be activating mutations, in contrast to in colorectal cancer, where amplifications are more common [68]. One study that examined preclinical models of ERBB2-mutated small bowel adenocarcinoma patient-derived xenografts and cell lines demonstrated activity from small molecular inhibitors of ERBB2 [69]. However, no clinical data are currently available assessing the efficacy of ERBB2-targeted therapy.

●RET fusions are rare in small bowel cancer [76]. However, in September 2022, the US Food and Drug Administration granted a tissue-agnostic, accelerated approval to the RET tyrosine kinase inhibitor selpercatinib, for adult patients with locally advanced or metastatic solid tumors, including small bowel cancers, with a RET gene fusion and disease progression on or following prior systemic treatment who have no satisfactory alternative treatment options. The phase I/II basket trial (LIBRETTO-001) of selpercatinib for RET fusion positive solid tumors included only two patients with small bowel cancer, but one had a complete clinical response [77].

Indications for immunotherapy — For patients whose tumors are dMMR or that have high levels of TMB (≥10 mutations/megabase), another option for chemotherapy-refractory disease is treatment with an immune checkpoint inhibitor that targets the programmed death receptor 1 (PD-1; ie, pembrolizumab). We do not suggest a trial of pembrolizumab for other groups of patients [78], unless in the context of a clinical trial.

Immunotherapeutic approaches to cancer therapy are based on the premise that the immune system plays a key role in surveillance and eradication of malignancy and that tumors evolve ways to elude the immune system. (See "Principles of cancer immunotherapy".)

●Deficient mismatch repair – Some cancers with deficient mismatch repair (dMMR) are particularly sensitive to immune-based therapies. Objective, in some instances complete, and durable responses to immune checkpoint inhibitors targeting the programmed cell death receptor 1 (PD-1; eg, pembrolizumab) have been reported in a variety of patients with dMMR cancers, including small bowel adenocarcinomas. The characteristic genetic signature of tumors with dMMR is a high number of DNA replication errors and high levels of DNA MSI. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

Mutations in one of several DNA MMR genes are found in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) and in some small bowel adenocarcinomas. (See "Pathology and prognostic determinants of colorectal cancer", section on 'Mismatch repair deficiency' and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Genetics'.)

The fraction of small intestine cancers that are dMMR has been addressed in the following reports:

•In one study, approximately 8 percent of small intestinal malignancies were dMMR or MSI-H [79].

•Variable levels of dMMR have been reported for small bowel tumors when the analysis has been limited to individuals with advanced/metastatic disease (1 percent in one study [79], 8 percent in a second [68], and approximately 16 percent in a third study [80]).

In the United States, pembrolizumab is approved for treatment of a variety of advanced solid tumors, including small bowel adenocarcinomas, that are MSI-H or dMMR, that have progressed following prior treatment, and for which there are no satisfactory alternative treatment options, the first such approval of a tissue-agnostic anticancer treatment. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

Efficacy in dMMR small intestine cancers was shown in the phase II KEYNOTE-158 study, which enrolled 19 patients with small bowel cancer [81]. There were eight objective responses (42 percent), three of which were complete, and the duration of response ranged from 4.3 to 13.3+ months.

An important point is that MSI-H or dMMR may indicate the presence of Lynch syndrome, an inherited condition that predisposes to several cancers, including small bowel adenocarcinoma. All patients with an MSI-H/dMMR small bowel adenocarcinoma should undergo germline genetic assessment for Lynch syndrome, regardless of age or family history [82]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Microsatellite instability testing'.)

The approach to testing for dMMR is addressed in detail elsewhere. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Assessing mismatch repair' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Approach to testing dMMR as a predictive marker'.)

●High tumor mutational burden – Tumors with a high tumor mutational burden (TMB) also appear to be sensitive to immune checkpoint inhibitors. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Tumor mutational burden'.)

Approximately 8 to 12 percent of small bowel adenocarcinomas have high levels of TMB, defined as ≥10 mutations per megabase (muts/mB) [68,83].

In June 2020, pembrolizumab was approved for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors, including small bowel adenocarcinomas, that are tissue TMB-high (≥10 mut/mB) and who have progressed following prior therapy and who have no satisfactory alternative treatment options. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Tumors with high mutational burden'.)

Treatment of the primary tumor — Palliative surgical resection of the primary tumor may be needed in patients with locally advanced unresectable or metastatic small bowel adenocarcinoma to manage bowel obstruction or bleeding. For tumors located in the duodenum, RT may provide local disease control or control of bleeding, and for nonsurgical palliation of duodenal obstruction, an endoscopic duodenal stent can be placed. (See "Enteral stents for the palliation of malignant gastroduodenal obstruction".)

Potentially resectable metastases — Potentially resectable metastases are rare with small bowel adenocarcinoma. Limited information is available regarding metastasectomy in this setting. Two series report no long-term survivors among a small number of patients undergoing surgery for hepatic metastases from small bowel adenocarcinoma [84,85]. On the other hand, potential benefit for hepatic resection is suggested by the following observations:

●Adam and colleagues reported encouraging data in a large series of patients with hepatic metastases from a noncolorectal cancer primary that included 28 patients with jejunal or ileal adenocarcinoma and 12 patients with a duodenal adenocarcinoma [86]. Five-year survival postresection was 49 percent for the jejunal/ileal group and 21 percent for the duodenal group.

●In a case-control study from Johns Hopkins evaluating the benefit of resection of synchronous hepatic metastases for periampullary tumors, two patients had duodenal adenocarcinoma, one of whom represented the longest survivor at 39.5 months [87].

Isolated peritoneal carcinomatosis — Long-term survival has been reported after aggressive cytoreduction surgery and intraperitoneal hyperthermic chemotherapy in highly selected patients with isolated peritoneal carcinomatosis from a small bowel adenocarcinoma [88-91]. One retrospective study of four tertiary referral centers in the Netherlands included 16 patients who underwent cytoreductive surgery and intraperitoneal hyperthermic chemotherapy [89]. Median disease-free survival was 9.5 months, and eight patients had a disease recurrence, although median follow-up time was short at only 16.5 months. Highly selected patients being considered for this approach should be referred to a center with expertise in the management of peritoneal surface malignancies. (See "Well-differentiated neuroendocrine tumors of the appendix" and "Malignant peritoneal mesothelioma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging".)

Post-treatment surveillance — There are no guidelines for post-treatment surveillance for small bowel adenocarcinoma from the American Society of Clinical Oncology (ASCO) or the European Society of Medical Oncology (ESMO). Guidelines from the NCCN generally follow a similar approach as for resected colon cancer, but with some exceptions [5] (see "Post-treatment surveillance after colorectal cancer treatment"):

●History and physical examination every 3 to 6 months for two years, then every 6 months for a total of five years

●Chest/abdomen/pelvic CT every 6 to 12 months for two years, then annually for a total of five years

●Assay of tumor markers CEA and/or CA 19-9-every 3 to 6 months for two years, then every 6 months for a total of five years

●Routine capsule endoscopy is not indicated

Most of the authors and editors associated with this topic review follow these guidelines. Patients can also be followed according to published post-treatment surveillance guidelines for colon cancer, which are available from several expert groups and are compared and contrasted in the table (table 8). (See "Post-treatment surveillance after colorectal cancer treatment".)

NEUROENDOCRINE TUMORS

Prognosis — Neuroendocrine tumors (NETs) arising in the jejunum and ileum are typically well differentiated and generally act as biologically indolent tumors. Five-year survival rates for small bowel NETs arising in the jejunum or ileum are between 52 and 100 percent depending on the stage of disease (table 9 and table 10) [21,36,92-94]. Rates may be lower for a clinical presentation of an ileal NET with a large mesenteric mass >2 cm (five-year survival rates 65 versus 93 percent in one series for those with and without a large mesenteric mass [95]). Duodenal primaries may have a more heterogeneous behavior regardless of lymphatic spread [96].

However, even among patients with distant metastasis, 10-year survival rates of 40 to 60 percent are reported. Ten-year disease-specific survival rates stratified according to the 2010 American Joint Committee on Cancer (AJCC) stage groupings from a series of 6792 patients with small intestine NETs derived from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry were as follows [97] (see "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Small intestine'):

●Stage I – 95 percent (95% CI 93-97 percent)

●Stage IIA – 95 percent (95% CI 90-96 percent)

●Stage IIB – 77 percent (95% CI 71-83 percent)

●Stage IIIA – 68 percent (95% CI 58-77 percent)

●Stage IIIB – 77 percent (95% CI 74-80 percent)

●Stage IV – 42 percent (95% CI 38-46 percent)

Treatment of locoregional disease — NETs of the small bowel have the potential to metastasize, even when <2 cm in size (table 11). In a survey of published literature in which tumor size was reported and a distinction made between metastases to the regional nodes and distant sites, small bowel NETs less than 1 cm in size had nodal and distant metastases present at discovery in 12 and 5 percent, respectively [92]. For tumors between 1.1 and 1.9 cm, nodal or distant metastases were present in 70 and 19 percent of patients, respectively, while NETs exceeding 2 cm were associated with nodal and distant metastases in 85 and 47 percent of cases, respectively. Similar results have been published by others [98]. Even higher rates of nodal metastases for lesions ≤1 cm are reported for duodenal NETs [99].

Because of this, the surgical management of small bowel NETs differs from that of appendiceal NETs (for which a local excision [appendectomy] is considered adequate for a tumor smaller than 1.5 to 2.0 cm in the absence of invasion of the mesoappendix, blood vessels, or regional nodes). (See "Well-differentiated neuroendocrine tumors of the appendix", section on 'Treatment of localized disease'.)

Most surgeons recommend a wide en bloc resection that includes the adjacent mesentery and lymph nodes for a small bowel NET of any size [100-106]. This operation may cure a greater proportion of patients, and it provides better local disease control. Such a resection may be difficult at times if fibrosis and foreshortening of the mesentery are present. Outcomes are better among patients who undergo complete (R0) resection (table 12) [107]. Retrieval of at least eight lymph nodes appears to be optimal to achieve accurate staging [108].

Since approximately 40 percent of patients with midgut NETs have a second gastrointestinal tract malignancy, the entire bowel and colon should be evaluated prior to any surgical intervention. Intraoperative assessment, including "running the bowel," should also be performed to exclude multiple sites of NETs of the small bowel. (See "Epidemiology, clinical features, and types of small bowel neoplasms" and "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Small intestine'.)

Treatment of advanced disease

Surgery — The role of surgery for metastatic NETs arising in the small bowel is not clearly defined. When metastatic disease is present (usually to the liver), it is necessary to establish whether the patient has symptoms of carcinoid syndrome and whether curative resection is possible. In an asymptomatic patient, if there are no contraindications to surgery, and the metastases appear resectable, then an attempt at complete extirpation is usually undertaken. Resection of hepatic metastases prolongs disease-free survival, and it may possibly increase overall survival as well. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)

Carcinoid syndrome is the term applied to a constellation of symptoms mediated by various humoral factors elaborated by NETs (table 13). Two of the most common manifestations are episodic flushing and diarrhea (table 14). Ninety percent of patients with NETs and the carcinoid syndrome have metastatic disease, typically to the liver. (See "Clinical features of carcinoid syndrome".)

Surgery plays a limited role in the treatment of most patients with the carcinoid syndrome because almost all have extensive unresectable metastatic disease. Symptomatic relief may be obtained by debulking surgery; however, the duration of effective relief from these palliative procedures can be short, usually less than 12 months. On the other hand, treatment with somatostatin analogs usually provides longer-term adequate symptomatic relief. (See 'Systemic therapy' below.)

The indications for resection of the primary site in patients with metastatic disease are not well established, and there is little consensus on this issue. In general, at the time of surgical resection of metastatic disease, it is recommended to resect a primary intestinal NET in order to prevent the development of complications such as bowel obstruction or intestinal ischemia; whether or not removal of the primary tumor improves survival is controversial. However, prophylactic surgery is usually not undertaken unless surgery is being performed for another reason, or if serial computed tomography (CT) scans demonstrate the development of fibrosing mesenteritis. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Management of the primary tumor in patients with metastatic disease'.)

Surgical procedures in patients with carcinoid syndrome are potentially hazardous due to the precipitation of carcinoid crisis during induction of anesthesia or surgical manipulation of tumors. Prevention and management of carcinoid crisis is addressed in detail elsewhere. (See "Treatment of the carcinoid syndrome", section on 'Carcinoid crisis: prevention and management'.)

Nonsurgical liver-directed therapy — Due to the hypervascular nature of NET metastases, hepatic arterial embolization is frequently applied as a palliative technique in patients with hepatic metastases who are not candidates for surgical resection. The response rates associated with bland embolization or chemoembolization, as measured either by decrease in hormonal secretion or by radiographic regression, are generally greater than 50 percent. However, the duration of response can be brief, ranging from 4 to 24 months in uncontrolled series. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)

Another form of nonsurgical liver-directed therapy is radioembolization using yttrium-labeled microspheres. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)

Systemic therapy — The systemic management of well-differentiated neuroendocrine tumors is discussed in more detail elsewhere. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring".)

Post-treatment surveillance — Clinical practice is variable with respect to post-treatment surveillance, particularly as to the use of serum tumor markers. Recommendations for post-treatment surveillance, including those from expert groups such as the National Comprehensive Cancer Network (NCCN) [109] and European Neuroendocrine Tumor Society (ENETS), are discussed in detail elsewhere. (See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Post-treatment follow-up'.)

SARCOMA — Malignant mesenchymal tumors of the gastrointestinal tract fall into two categories:

●Gastrointestinal stromal tumors (GIST), which comprise >85 percent of all sarcomas arising within the gastrointestinal tract

●The various other soft tissue sarcomas that arise at other sites, including leiomyosarcoma, fibrosarcoma, liposarcoma, Kaposi sarcoma, and angiosarcoma, collectively referred to as non-GIST gastrointestinal sarcomas

GISTs and leiomyosarcomas can have a similar morphologic appearance, but their distinction is important because treatment, particularly in the setting of advanced disease, differs markedly. Approximately 85 percent of GISTs have activating mutations in the KIT protooncogene, which leads to constitutive expression of KIT, a receptor tyrosine kinase. A subset of GISTs lacking KIT mutations have activating mutations in a related receptor tyrosine kinase, the platelet-derived growth factor receptor alpha (PDGFRA) gene. (See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors", section on 'Pathogenesis'.)

Imatinib mesylate is a selective inhibitor of KIT and PDGFRA, and has become the first-line therapy for advanced GIST. For localized cases that are borderline resectable or for which surgical resection might result in significant functional deficit (eg, loss of the esophagogastric junction), initial (neoadjuvant) imatinib may be considered. Testing the tumor for mutation is recommended prior to starting preoperative imatinib to ensure that the tumor has a genotype that will respond to treatment. For localized GIST, which are potentially resectable with negative margins and minimal morbidity, surgical resection is the preferred initial therapy. (See "Diagnosis and staging of small bowel neoplasms", section on 'Histology and differential diagnosis' and "Adjuvant and neoadjuvant therapy for gastrointestinal stromal tumors" and "Local treatment for gastrointestinal stromal tumors, leiomyomas, and leiomyosarcomas of the gastrointestinal tract".)

Surgery — Surgical treatment for localized, potentially resectable GISTs and non-GIST primary sarcomas of the small bowel is similar. In general, en bloc segmental resection with tumor-free margins is the primary treatment modality for both and preferred over peritumoral resection. Every effort should be made not to violate the pseudocapsule of the tumor to avoid spillage of the tumor. If laparoscopic surgery is performed, the tumor should be extracted in an Endocatch bag to avoid tumor spillage or seeding of port sites. Unlike adenocarcinomas and neuroendocrine tumors, sarcomas infrequently metastasize to regional mesenteric lymph nodes, and routine mesenteric lymphadenectomy is neither necessary nor beneficial. (See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors" and "Local treatment for gastrointestinal stromal tumors, leiomyomas, and leiomyosarcomas of the gastrointestinal tract", section on 'Small intestine'.)

Adjuvant and neoadjuvant treatment — Before 2001, surgery was the only available treatment for GISTs. However, in approximately one-half of patients, complete resection was not possible, and median survival ranged from 10 to 23 months. Dramatic improvements in tumor control occurred with the recognition that mutational activation of KIT or a second receptor tyrosine kinase, PDGFRA, stimulated the growth of these cancer cells, and that growth could be inhibited with orally active small molecule tyrosine kinase inhibitors (TKIs) such as imatinib. Among patients with overt metastatic disease, 80 percent experience an objective response or disease stability, median progression-free survival (PFS) is 20 to 26 months, and median overall survival is 51 to 57 months. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors".)

The success of these agents in the setting of advanced disease prompted interest in their use as adjuvant therapy after complete resection of a GIST or as preoperative (induction or neoadjuvant) therapy in patients with locally advanced disease:

●For most patients with activating KIT mutations, adjuvant imatinib is recommended for at least three years following resection of a high-risk GIST. This recommendation is based on the results of the Scandinavian Sarcoma Group (SSG) XVIII trial, which compared 36 versus 12 months of adjuvant imatinib (400 mg daily) in 400 patients with a high-risk resected GIST (defined according to the modified consensus criteria [110] as having at least one of the following: tumor size >10 cm, mitotic count >10 per 50 high-power fields [HPF], tumor size >5 cm with mitotic rate >5 per 50 HPF, or tumor rupture) [111]. Prolonged treatment was associated with a significant improvement in relapse-free survival as well as overall survival. (See "Adjuvant and neoadjuvant therapy for gastrointestinal stromal tumors", section on 'Benefit of imatinib'.)

●For patients with locally advanced disease, preoperative imatinib has been recommended as a treatment strategy to facilitate resection and decrease surgical morbidity of the resection by reducing the need for multivisceral resection, and diminish the risk of preoperative tumor rupture and intraoperative spillage of live tumor cells. However, a disadvantage of preoperative imatinib is the inability to fully assess tumoral mitotic rate, a major prognostic factor. (See "Adjuvant and neoadjuvant therapy for gastrointestinal stromal tumors", section on 'Neoadjuvant therapy'.)

The role of adjuvant or neoadjuvant chemotherapy for small bowel sarcomas other than GIST tumors is undefined.

Prognosis — Small bowel GISTs have been long considered to have an inferior prognosis as compared with those arising in the stomach. However, more recent data have challenged this notion. A study utilizing the Surveillance, Epidemiology, and End Results (SEER) database from 2002 to 2012 reported on 3759 patients with gastric GIST and 1848 patients with small intestine GIST [112]. Five-year survival was 83.3 percent for small intestine GIST, compared with 82.2 percent for gastric GIST. On multivariable analysis, male sex, nodal disease, and radiation therapy were the only negative prognostic factors for small intestine GIST patients. Black American patients survived only approximately half as long as White American patients.

The prognosis of small intestine GISTs depends on the tumor site, adequacy of resection, tumor size, and mitotic activity (table 15A-B). The Memorial Sloan Kettering Cancer Center offers a GIST nomogram designed to predict the likelihood of tumor recurrence two and five years following complete resection without the addition of TKIs. (See "Adjuvant and neoadjuvant therapy for gastrointestinal stromal tumors", section on 'Estimation of recurrence risk' and "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors", section on 'Prognostic and risk stratification models'.)

Post-treatment surveillance — There are no evidence-based guidelines on what constitutes appropriate follow-up after treatment of a GIST, and there is no consensus on this issue. Recommendations, including those from expert groups such as the National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO), are discussed in detail elsewhere. (See "Local treatment for gastrointestinal stromal tumors, leiomyomas, and leiomyosarcomas of the gastrointestinal tract", section on 'GIST'.)

LYMPHOMA — Primary gastrointestinal (GI) lymphomas can be operationally defined as lymphomas in which the main bulk of disease is confined to the GI tract. The most common subtypes of primary small intestinal non-Hodgkin lymphoma are diffuse large B cell lymphoma, enteropathy-associated T cell intestinal lymphoma, extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT), mantle cell lymphoma, and Burkitt and Burkitt-like lymphoma. Hodgkin lymphoma is extremely rare. (See "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)".)

The pathology, clinical features, and prognosis of intestinal lymphomas may differ from lymphomas of lymph node origin. As an example, indolent lymphomas of lymph node origin are almost always disseminated at diagnosis, have frequent bone marrow involvement, generally respond to therapy, but continuously recur. Median survival can exceed 10 years, although cure is unusual. On the other hand, MALT and MALT-type lymphomas, also considered indolent forms of lymphoma, are often localized at diagnosis, and long-term disease-free survival and cure are common. (See "Classification of hematopoietic neoplasms".)

Nevertheless, the treatment approach to a small bowel lymphoma generally parallels the standard treatment approach for that histologic subtype of lymphoma arising in nodal regions. The unique situation that can arise in patients with lymphoma of the small intestine is in patients who undergo surgical resection of localized stage IE or IIE disease (table 16) for diagnostic purposes or because of the presence of obstruction or perforation. In such cases, outcomes following surgery alone are poor with five-year survival rates of approximately 45 percent for stage IE disease and 19 percent for stage IIE disease. Systemic chemotherapy is indicated in this situation, even if resection is complete.

The management and chemotherapy approach for lymphomas involving the GI tract is discussed in detail elsewhere. (See "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)".)

METASTATIC LESIONS — Involvement of the small bowel is not uncommon in the context of widespread peritoneal carcinomatosis. However, hematogenous spread of metastatic disease to the small intestine is rare. In studies in which direct extension from an adjacent primary tumor was excluded, the most common cancers to involve the small bowel were melanoma, lung, breast, cervix, sarcoma, and colon [113-115].

Treatment of these lesions is palliative; limited resection or intestinal bypass may be needed to relieve symptoms. For nonsurgical palliation of duodenal obstruction, an endoscopic duodenal stent can be placed. (See "Enteral stents for the palliation of malignant gastroduodenal obstruction".)

TREATMENT OF BENIGN NEOPLASMS — Treatment recommendations for benign neoplasms arising in the small bowel vary from endoscopic removal to radical resection (eg, pancreaticoduodenectomy or duodenectomy), depending on the type of neoplasm, size, location, number, and malignant potential.

Adenoma — In general, simple tubular adenomas and Brunner gland tumors have a low malignant potential; they can be cured by endoscopic polypectomy, simple local resection, or submucosal resection [116,117]. Villous adenomas have a malignant potential similar to their colonic counterparts; up to 30 percent may harbor malignancy, depending on size. Nevertheless, endoscopic polypectomy or simple resection is sufficient as long as no invasive carcinoma is found in the specimen [116-118].

Many clinicians advocate radical pancreaticoduodenectomy for periampullary duodenal villous adenomas because of the difficulty in making a preoperative diagnosis and in obtaining an adequate resection without sacrificing the ampulla. However, one study found that local submucosal excision produced acceptable long-term results if the tumor did not have areas of invasive cancer; 17 percent recurred after five years of follow-up [119]. Periampullary adenomas containing areas of malignant growth (in situ or invasive) still require radical surgery. (See "Ampullary adenomas: Management".)

For patients who have duodenal adenomas in the setting of familial adenomatous polyposis (FAP), there have been attempts to identify those at greatest risk for the development of adenocarcinoma of the duodenum. A classification system (the modified Spigelman classification (table 17)) recognizes five grade scales (stages O to IV) based on the number of polyps (1 to 4, 4 to 20, >20), their size in mm (1 to 4, 5 to 10, and >10), histology (tubular, tubulovillous, villous), and severity of dysplasia (mild, moderate, severe) [120]. Patients with stage IV disease appear to be at the greatest risk for developing adenocarcinoma, leading some authors to recommend prophylactic duodenectomy in this setting, although this is a controversial area. (See "Familial adenomatous polyposis: Screening and management of patients and families", section on 'Upper gastrointestinal tumors'.)

Leiomyoma — Small bowel leiomyomas occur most frequently in the jejunum, and they may reach considerable and even palpable size by the time they are diagnosed (image 1 and picture 1). Histologically, these tumors are often difficult to distinguish from malignant leiomyosarcomas, although the distinction is important from the standpoint of resection extent.

Determination of tumor grade may be used to assist in treatment decisions. In a series of 131 patients, for example, a mitotic index (MI) ≥2 (defined as the number of mitoses per 50 high power fields [HPF]) identified a population of patients who benefited from more extensive surgery [121]. Despite conservative resection in 67 percent of these patients, there were no recurrences in those who had a MI <2, compared with 16 percent in patients with a higher MI.

Lipoma — Small bowel lipomas can produce many complications, including obscure gastrointestinal bleeding. Lipomas of the small bowel have no malignant potential. Excision is required only if symptomatic; incidentally discovered tumors should be left untreated.

Hamartomas and Peutz-Jeghers syndrome — Peutz-Jeghers syndrome is an inherited disorder characterized by mucocutaneous melanotic pigmentation and gastrointestinal polyps. The lesions are hamartomas that occur primarily in the jejunum and ileum. There are few reports of malignant transformation. Surgical treatment is limited to the segment responsible for symptoms [118,122]. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Soft tissue sarcoma".)

SUMMARY AND RECOMMENDATIONS

●A variety of malignant (eg, adenocarcinomas, neuroendocrine tumors, gastrointestinal stromal tumors [GISTs] and non-GIST soft tissue sarcomas, and lymphomas) and benign neoplasms (eg, adenomas, leiomyomas, and lipomas) arise within the small bowel. (See "Epidemiology, clinical features, and types of small bowel neoplasms".)

●The diagnosis of a small bowel tumor is often made late in the course of the disease because of their rarity and nonspecificity of symptoms (abdominal pain, weight loss, nausea and vomiting, occult gastrointestinal tract bleeding) (See "Diagnosis and staging of small bowel neoplasms".)

●The following represent our approach to treatment for each tumor type:

●Adenocarcinoma

•Surgery

For localized adenocarcinomas of the second portion of the duodenum, we recommend pancreaticoduodenectomy rather than segmental resection (Grade 1B). We suggest segmental resection rather than pancreaticoduodenectomy for lesions in the first, third and fourth portion of the duodenum, if negative resection margins can be achieved (Grade 2C). (See 'Duodenal tumors' above.)

Adenocarcinomas involving the jejunum or proximal ileum require wide excision of the malignancy and surrounding tissues at risk for contiguous spread. Tumors of the distal ileum require resection of the ileocolic artery and associated regional lymph nodes. (See 'Locoregional disease' above.)

•Perioperative therapy

-For all patients with lymph node-positive, completely resected small bowel adenocarcinoma, we suggest six months of postoperative oxaliplatin-containing adjuvant chemotherapy (Grade 2C). (See 'Adjuvant therapy' above.)

-For patients with node-positive duodenal primaries, we suggest fluoropyrimidine-based chemoradiotherapy in addition to adjuvant oxaliplatin-containing systemic chemotherapy (Grade 2C). (See 'Chemoradiotherapy for duodenal primaries' above.)

-For patients with completely resected T3 or T4 node-negative resected small bowel adenocarcinomas, observation or six months of adjuvant chemotherapy are both acceptable options, and we base our decision-making on clinicopathologic features, the presence or absence of deficient mismatch repair (dMMR), and patient preference. If adjuvant chemotherapy is chosen for node-negative disease, we suggest a fluoropyrimidine alone (capecitabine, leucovorin-modulated FU), as long as the tumor has proficient MMR. In the setting of dMMR, we suggest an oxaliplatin-containing regimen rather than a fluoropyrimidine alone (Grade 2C). (See 'Adjuvant therapy' above.)

-We consider neoadjuvant therapy on a case-by-case basis in patients with bulky or locally advanced disease. (See 'Indications for neoadjuvant therapy' above.)

•Unresectable or metastatic disease

-For patients who are able to tolerate it, we suggest systemic chemotherapy rather than supportive care alone (Grade 2B). We use an oxaliplatin-based chemotherapy regimen as a first-line regimen. (See 'Systemic therapy' above.)

-Hepatic resection is a reasonable option for selected patients with potentially resectable liver metastases, a controlled primary site, and no extrahepatic metastases. (See 'Potentially resectable metastases' above.)

●Sarcoma

•We recommend en bloc segmental resection with tumor-free margins rather than peritumoral resection as the primary treatment modality for most resectable GISTs and other primary sarcomas of the small bowel (Grade 1B). We suggest initial imatinib rather than upfront surgery for a borderline resectable or unresectable but non-metastatic small bowel GIST tumor (Grade 2B). (See 'Sarcoma' above.)

•The risks, benefits, and recommendations regarding the use of adjuvant imatinib following complete resection of a GIST are discussed elsewhere. (See "Adjuvant and neoadjuvant therapy for gastrointestinal stromal tumors".)

●Neuroendocrine tumors

•We recommend wide en bloc segmental resection that includes the adjacent mesentery and lymph nodes for small bowel neuroendocrine tumors of any size rather than local excision alone (Grade 1B).

•The entire bowel and colon should be evaluated prior to and during any surgical intervention given the high rate of concurrent GI neoplasms. (See 'Treatment of locoregional disease' above.)

●Lymphoma

•In general, the treatment approach for extranodal involvement of the intestinal tract by a lymphoma generally parallels the treatment approach for that histologic subtype of lymphoma arising in nodal regions. (See "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)".)

●Benign lesions

•Management of benign small bowel lesions must be tailored to their size, number, location, malignant potential, and whether they are symptomatic.

•For simple tubular adenomas, Brunner gland adenomas, and villous adenomas with no evidence of in situ or invasive malignancy, we recommend endoscopic polypectomy, submucosal resection, or simple local resection rather than more radical resection (Grade 1B). We recommend radical resection for villous adenomas containing areas of malignant growth (in situ or invasive) (Grade 1B). (See 'Adenoma' above.)

Recommendations regarding management of duodenal adenomas in patients with familial adenomatous polyposis (FAP) are provided elsewhere. (See "Familial adenomatous polyposis: Screening and management of patients and families".)

•For most small bowel leiomyomas we recommend open surgical resection rather than observation due to the difficulty in excluding leiomyosarcoma or a GIST tumor (Grade 1B). (See 'Leiomyoma' above.)

•For lipomas, we suggest excision only if the lesion is symptomatic (Grade 2C). (See 'Lipoma' above.)