Advances in Small Bowel Cancer Generate New NCCN Guidelines

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Article
Oncology Live®Vol. 20/No. 20
Volume 20
Issue 20

A new set of recommendations for the treatment of small bowel adenocarcinoma, a relatively rare type cancer of the gastrointestinal tract, have been created by the National Comprehensive Cancer Network. The guidelines are the first in the United States and second in the world to recommend treatments specific to the malignancy, which is often diagnosed at advanced stages.

Katrina S. Pedersen,
MD, MS

Katrina S. Pedersen, MD, MS

Katrina S. Pedersen, MD, MS

A new set of recommendations for the treatment of small bowel adenocarcinoma (SBA), a relatively rare type cancer of the gastrointestinal (GI) tract, have been created by the National Comprehensive Cancer Network (NCCN). The guidelines are the first in the United States and second in the world to recommend treatments specific to the malignancy, which is often diagnosed at advanced stages.

Historical management of the disease followed recommendations for colorectal cancer (CRC); however, advancements in next generation sequencing have provided insights into tumor biology that call for standardization in the diagnosis, staging, and treatment options for patients with SBA.

Katrina S. Pedersen, MD, MS, a member of the NCCN Guidelines Panel for Colorectal Cancer, said that the timing for these guidelines felt right during an interview with OncologyLive®. “We found that the genomic underpinnings involved with this cancer are not necessarily the same as colorectal cancer,” said Pedersen, an assistant professor of medicine, Division of Medical Oncology, Washington University School of Medicine in St. Louis, Missouri.

The incidence of small bowel cancers is rising at an annual percent increase of 1.8 in contrast to the downward trend for other GI malignancies such as esophageal, colon, and rectum. It is estimated that 10,590 new cases of small bowel cancer will occur in the United States in 2019, and 1590 patients will die of the disease. SBA accounts for 30% to 40% of cases of small intestinal cancer affecting men and women almost equally, with an incidence of 2.6 per 100,000 men and 2.0 per 100,000 women.1

Highlighting further differences between GI cancer types, Pedersen said the new NCCN guidelines place greater emphasis on taxanes, which are more active in SBA than CRC, and recommend avoiding EGFR inhibitors in the SBA setting.

Work-Up and Treatment

In SBA, the majority of tumors arise in the duodenum. The NCCN guidelines for SBA suggest a workup that includes mismatch repair (MMR) or microsatellite instability (MSI) testing, abdominal/pelvic computed tomography or magnetic resonance imaging, biopsy with pathology review, complete blood count, and chemistry profile.1 Pedersen emphasized that carbohydrate antigen 19-9 can be a more relevant tumor marker in these cancers.

The mainstay of treatment for SBA is surgical resection, as the ability to completely resect the disease remains one of the most important prognostic factors for survival.2

For locally unresectable or medically inoperable disease, the new guidelines recommend the following neoadjuvant chemotherapies (with the goal of conversion to resectable disease): folinic acid, fluorouracil (5-FU), and oxaliplatin (FOLFOX), capecitabine plus oxaliplatin (CAPEOX), folinic acid, 5-FU, oxaliplatin, and irinotecan (FOLFOXIRI), or chemoradiation with capecitabine or infusional 5-FU. In the metastatic disease setting, the guidelines generally recommend palliative therapy with systemic drug therapy.1

“Not surprisingly, [because] this is a gastrointestinal cancer, FOLFOX plays an important role, as does cytotoxic chemotherapy in general,” Pedersen said.

Although FOLFOX and FOLFIRI (folinic acid, 5-FU, and irinotecan) produce relatively equivalent results in advanced CRC, Pedersen noted a lack of prospective data supporting the use of FOLFIRI in the frontline setting for SBA. “It’s an active [area of research], there’s no question about that, but we felt that the data supported the use of FOLFOX as the preferred regimen.”

Adjuvant Therapy

The use of adjuvant chemotherapy in the management of SBA remains unproven and awaits the results of the BALLAD trial.3 This phase III study is investigating the role of adjuvant 5-FU/ LV (leucovorin) or FOLFOX compared with observation alone in the treatment of patients with stage I to III SBA. Prior to the launch of BALLAD, retrospective studies and meta-analyses that assessed the efficacy of adjuvant therapy had mixed results.

Table. NCCN Adjuvant Therapy Recommendations for SBA1 (Click to Enlarge)

The NCCN recommendations for adjuvant therapy include the following: 6 months of FOLFOX, CAPEOX, 5-FU/LV, or capecitabine for any locally advanced SBA with positive lymph nodes (stage III); observation or 6 months of FOLFOX, CAPEOX, 5-FU/ LV, or capecitabine for stage II tumors that are microsatellite stable (MSS) or MMR proficient (pMMR) and have high-risk features, including T4 stage, close or positive surgical margins, few lymph nodes examined, or tumor perforation; observation or 6 months of 5-FU/ LV or capecitabine for T3, N0, M0 (stage IIA) tumors that are MSS or pMMR; and observation following surgery for all stage I tumors and stage II tumors that are MSI high.1

Immunotherapy: ZEBRA Trial

Pedersen also highlighted findings from the ZEBRA trial,4 in which pembrolizumab (Keytruda) failed to achieve the target response rate in pretreated patients with SBA but did control disease in some patients with MSS tumors. She noted that the data have not been formally reviewed by the NCCN committee yet, as the guidelines were finalized prior to the trial’s data embargo being lifted. Findings were presented during the European Society for Medical Oncology 21st World Congress on Gastrointestinal Cancer, held July 3 to 6, 2019, in Barcelona, Spain.4

Pedersen et al reported on 26 of 40 (65%) patients with known MSI status. The researchers reported that 32 patients were off study due to disease progress (25; 78%), death (5; 16%), and adverse effects (2; 6%). The median overall survival (OS) was 6.9 months (95% CI, 5.1-not reached), and the median progression-free survival (PFS) was 2.8 months (95% CI, 2.7-5.1). OS and PFS was similar among the 3 primary tumor sites.

Among 20 patients with MSS disease, there was 1 (6%) patient with a confirmed partial response (PR), 1 (6%) with an unconfirmed PR, and a disease control rate of 50% (10 patients with PR or stable disease). The investigators reported that half of the patients (2/4) with MSI-high status achieved a PR and remain alive without progression at the time of the presentation. Twenty-three (58%) patients had grade ≥3 AEs, and 9 (23%) patients had grade 4/5 AEs. Among patients with grade 5 AEs, all were deemed most likely secondary to disease progression; 1 patient had sepsis (grade 5) that was judged to be possibly treatment related.4

Risk Factors

The NCCN guidelines note that risk factors for SBA are similar to those for CRC and include lifestyle factors, inflammatory bowel disease, and certain familial syndromes, notably Lynch syndrome.1 Nonetheless, questions remain regarding risk factors for SBA, said Pedersen. “We think the immune system plays a protective role because of highly active immunosurveillance in the small intestine,” Pedersen said. “That might be one reason that fewer people develop SBA to the degree that people develop large intestine cancer.”

Lifestyle factors include high levels of alcohol consumption, smoking, and dietary factors such as low intake of fiber and high intake of red or processed meat. People with inflammatory bowel disease (ulcerative colitis or Crohn’s disease) are at increased risk for CRC, and several studies have reported an increased risk of distal SBA in patients with these diseases.

The guidelines also recommend that all patients with a personal history of SBA should be counseled for familial malignancies and considered for risk assessment of various genetic syndromes, including Lynch syndrome, familial adenomatous polyposis, and Peutz-Jeghers syndrome.1

Although there have been few established guidelines for SBA to this point, it is hoped that with their creation, patients with these rare cancers may be treated in the best manner possible, said Pedersen.

References

  1. NCCN Clinical Practice Guidelines in Oncology. Small Bowel Adenocarcinoma, version 1.2020. National Comprehensive Cancer Network website. bit.ly/2lwOxwl. Published July 30, 2019. Accessed August 9, 2019.
  2. Noone AM, Howlander, N, Krapcho M, et al. SEER Cancer Statistics Review (CSR), 1975-2015. Surveillance, Epidemiology, and End Results Program website. bit.ly/2ktXlCU. Published September 10, 2018. Accessed August 19, 2019.
  3. Phase III Trial Investigating the Potential Benefit of Adjuvant Chemotherapy for Small Bowel Adenocarcinoma (BALLAD). bit.ly/2jZu5DS. Updated July 20, 2015. Accessed August 14, 2019.
  4. Pedersen K, Foster N, Overman M, et al. ZEBRA: an ACCRU/IRCI multicenter phase 2 study of pembrolizumab in patients with advanced small bowel adenocarcinoma (SBA). Presented at: the ESMO 21st World Congress on Gastrointestinal Cancer; July 3-6, 2019; Barcelona, Spain. Abstract O-007. bit.ly/2lxVwVZ.

“We hope that the trial will, in time, give us a clear-cut answer about the best way to approach adjuvant therapy for these patients,” Pedersen said. She also recommended, as emphasized by the NCCN guidelines, that radiation therapy should be considered only in specific cases, since results from retrospective studies suggest that it would not benefit the majority of patients with SBA (Table).1

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Katrina S. Pedersen, MD, MS, associate professor, John T. Milliken Department of Medicine, Division of Oncology, Medical Oncology program leader, cofounder, Young Onset Colorectal Cancer Program, Washington University School of Medicine in St. Louis, Siteman Cancer Center
Riccardo Lencioni, MD, FSIR, EBIR
Manish A. Shah, MD
Dae Won Kim, MD, Gastrointestinal Oncology Program, Moffitt Cancer Center
Michael J. Overman, MD, The University of Texas MD Anderson Cancer Center,
John Michael Bryant, MD,
Jacob Shreve, MD, MS, hematology/oncology fellow, Mayo Clinic
Efrat Dotan, MD, Fox Chase Cancer Center
A panel of 4 experts on gastrointestinal cancers
A panel of 4 experts on gastrointestinal cancers