Rare gastrointestinal (GI) cancers present unique challenges in diagnosis, treatment and research. To gain insight into these diseases, we spoke with Dr. Benjamin Weinberg (Georgetown University, Washington, DC, USA), an international expert in colorectal and pancreatic cancers, about three of the rarest GI cancers: small bowel, appendix and anal cancer.
Q1. How do we define ‘rare’ cancers, and where do these GI cancers fit in?
The National Cancer Institute defines a cancer as rare if it occurs in 15 or fewer cases per 100,000 individuals annually. Interestingly, most GI cancers technically meet this definition, with the notable exception of colorectal cancer. While we don’t typically think of pancreatic, hepatobiliary, stomach or esophageal cancers as ‘rare’, there are other GI cancers, such as small bowel, appendix and anal cancers, that clearly fall into this category. These tumours are not only uncommon but also challenging to diagnose and study due to their rarity and heterogeneity.
Q2. Small bowel cancer is one of the rarer GI cancers. What do we know about its incidence and treatment?
Small bowel cancer is much rarer than colorectal cancer, with an incidence of fewer than three cases per 100,000 people. Despite its rarity, its incidence is rising. The five-year survival rate for all cases is around 70%, according to the Surveillance, Epidemiology, and End Results (SEER) database.
The small intestine’s biology might help explain its lower cancer incidence compared to the colon. It has more immune cells and is less exposed to chronic inflammation. When small bowel cancer does develop, it is often adenocarcinoma, which we typically treat by extrapolating from colorectal cancer therapies. In the post-surgical setting, early-stage tumours may be managed with observation, while more advanced cases are treated with combination chemotherapy, such as fluoropyrimidine and oxaliplatin. In metastatic disease, regimens like FOLFOX, CAPOX or FOLFIRI are used, though targeted treatments are still being explored.
Q3. Appendix cancer is often discovered incidentally. What are the treatment considerations?
Yes, appendix cancer is frequently found during surgery for appendicitis. Once diagnosed, pathologists determine its subtype, with adenocarcinoma being the most aggressive form. If the tumour is advanced, patients may need a right hemicolectomy with lymph node sampling.
Appendix cancer is often a peritoneal disease, meaning tumours can spread within the abdominal cavity. Standard chemotherapy is not always effective, particularly for mucinous subtypes. For these cases, we rely on cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC), a heated chemotherapy applied directly into the abdominal cavity. While systemic chemotherapy is an option for metastatic cases, surgery remains the primary treatment for many patients.
Q4. Anal cancer is different from other GI cancers. How is it typically managed?
Anal cancer arises from squamous cells and is actually more closely related to skin cancers than colorectal cancer. It is often caused by the human papillomavirus (HPV), making it more immunogenic than other GI cancers.
For localized anal cancer, we use chemoradiation – typically fluoropyrimidine and mitomycin combined with radiation – to avoid extensive surgery that could require a permanent colostomy. If the tumour does not respond, a salvage abdominal perineal resection is considered.
When anal cancer spreads, we use systemic chemotherapy with carboplatin and paclitaxel. Immunotherapy has shown promise, particularly for HPV-driven cases. Nivolumab and pembrolizumab have been effective in some patients, although combination immunotherapy approaches have not yet shown significant survival benefits.
Q5: Given the rarity of these cancers, what are the main research challenges, and how can advocacy help?
The biggest challenge is the lack of large-scale clinical trials, meaning we often rely on data from colorectal cancer studies. This is why precision medicine approaches, such as next-generation sequencing, are crucial in identifying targeted treatments.
For small bowel cancer, detecting mismatch repair deficiency is key since these patients may respond better to immunotherapy. In anal cancer, targeting HPV-related pathways could open new treatment options. Appendix cancer research is focusing on optimizing surgical and chemotherapy combinations.
Because these cancers are rare, advocacy groups help raise awareness and funding research. Organizations like the Colorectal Cancer Alliance and FIGHT CRC have formed the GI Cancers Alliance, bringing together smaller patient communities to ensure these diseases receive the attention they deserve.
By leveraging precision medicine, expanding research collaborations and supporting advocacy efforts, the hope is to improve treatment options and outcomes for patients with these rare GI cancers.
Disclosure: Benjamin Weinberg has no financial or non-financial conflicts of interest to declare in relation to this article.
Cite: Q&A with Dr Benjamin Weinberg: Understanding rare GI cancers (small bowel, appendix and anal cancer). touchONCOLOGY. March 26th, 2025
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