What are the latest pharmacotherapy options for small bowel adenocarcinoma?

Abstract

Incidence of small bowel adenocarcinoma is slowly but steadily increasing. As we gain more knowledge of the molecular basis of this disease, we may be able to approach it via using novel biologic or targeted therapies with or without traditional chemotherapy agents. In the meantime, early diagnosis is still best as it prompts early surgical resection and offers potential cure. The role of adjuvant and neoadjuvant therapy is currently being explored in clinical trials. Several clinical trials have suggested that first-line chemotherapy for patients with metastatic disease should consist of either 5-fluorouracil-leucovorin-oxalipatin or capecitabine-oxaliplatin, while 5-fluorouracil-leucovorin-irinotecan can be reserved for second-line treatment. However, we realize the limitations of these studies, given their small sample size and/or retrospective nature. Single-agent 5-fluorouracil/capecitabine should be considered in patients who are either intolerant to or experience significant side effects with oxaliplatin or irinotecan. We believe that cancers originating in the ampulla of Vater probably deserve a prospective randomized trial of cisplatin-gemcitabine, the current standard of therapy for advanced biliary malignancies.

Keywords::

• adenocarcinoma/drug therapy
• fluorouracil/therapeutic use
• intestinal neoplasms/diagnosis
• intestinal neoplasms/drug therapy
• intestine small/pathology

Discussion

The small bowel, situated between the stomach and large intestine, constitutes 75% of the length and 90% of the mucosal absorptive surface of the alimentary tract [1]. However, small bowel malignancies account for only 3% of all gastrointestinal cancers and small bowel adenocarcinomas represent one-third of all small bowel cancers [2]. Although this malignancy is rare, its incidence has been steadily rising. The duodenum is the most frequently involved site (52 – 82%) followed by the jejunum (11 – 25%) and the ileum (7 – 13%) [3,4]. Herein, we expand the discussion on the treatment of small bowel adenocarcinoma initiated 3 years ago and give the reader an update on the management of this cancer type.

Patients with small bowel adenocarcinomas usually present late in the course of their disease due to nonspecific signs and symptoms, with an average delay in diagnosis of 4 – 7 months [1]. Different variables such as site of disease, stage at presentation, available expertise, patient comorbidities and performance status affect the treatment options for small bowel adenocarcinoma [2]. Tumor stage remains the most important prognostic factor in this malignancy [3]. Other adverse prognostic indicators include poor cell differentiation, positive surgical margins, duodenal location, male gender, black ethnicity and older age [5]. For locally advanced small bowel adenocarcinoma, lymph node invasion is the main prognostic indicator [3]. Recent data from the surveillance, epidemiology and end results database demonstrated improved outcomes with increased nodal sampling. In both locally advanced small bowel adenocarcinomas treated with adjuvant chemotherapy and metastatic disease, decreased performance status and increased serum levels of carcinoembryonic antigen or CA 19-9 correlated with reduced survival rates [6].

In localized tumors, complete resection of the primary tumor with regional lymph node resection is the mainstay of therapy [7]. The 5-year survival in patients who underwent resection was 54% compared with 0% in individuals treated with no surgery [8]. For tumors involving the first or second part of the duodenum, a Whipple procedure or pancreaticoduodenectomy is usually performed [2]. For lesions involving the third and fourth portions of the duodenum, wide local excision with regional lymphadenectomy is advised provided that negative margins and adequate lymph node sampling are achieved [2]. However, if the patient has retroperitoneal expansion, 2 – 3 months of neoadjuvant chemotherapy shall be considered [7]. The role of adjuvant chemotherapy remains controversial. There are no finalized prospective randomized controlled studies in this regard yet; however, data from the National Cancer Database show an increase in the use of adjuvant chemotherapy [2]. The adjuvant chemotherapy use increased from 8.1% in 1985 to 22.2% in 2005 (p < 0.0001) [5]. This shift is likely due to extrapolation of data from colorectal cancer showing a benefit of adjuvant chemotherapy as well as the known effectiveness of systemic fluoropyrimidine-based chemotherapy in the metastatic setting [9]. BALLAD is a Phase III prospective open-label randomized multicenter study sponsored by the Cancer Research United Kingdom/National Cancer Research Network/National Cancer Institute/European Organization for Research and Treatment of Cancer International Rare Cancers Initiative set to evaluate the role of adjuvant chemotherapy in patients with resected small bowel adenocarcinoma [9]. Hopefully, at the completion of this study in August 2022, we will gain insights on the role of adjuvant chemotherapy in this setting.

Adjuvant chemotherapy with concurrent radiation therapy has also been used in patients with duodenal adenocarcinoma in some centers, although studies in this regard are limited [9]. A retrospective analysis of a series of 32 patients found a trend for an improved 5-year overall survival (OS) in patients who underwent complete resection and received adjuvant or neoadjuvant 5-fluorouracil (5-FU) with concurrent radiation therapy compared with patients treated with surgery alone (OS of 83 vs 53%, p = 0.07) [10]. Another retrospective study of 10 patients concluded that neoadjuvant therapy helped convert unresectable duodenal adenocarcinoma to resectable disease [11]. These studies suggest that 5-FU-based chemotherapy with or without radiation therapy given adjuvantly or neoadjuvantly to patients with small bowel adenocarcinoma warrants further investigation [10,11].

The backbone of therapy for metastatic small bowel adenocarcinoma has been systemic chemotherapy (Table 1) [1,2]. Surgical resection at this juncture is only limited to the treatment of obstruction, bleeding, perforation or palliation of symptoms [1]. Regrettably, there are no randomized controlled trials that compared the outcomes seen with the use of chemotherapy as opposed to supportive care alone [2]. However, multiple retrospective studies have shown improved survival in patients who received chemotherapy. For instance, a retrospective study of 49 patients showed an OS of 12 months in the treated patient cohort as opposed to circa 2 months in untreated patients (p = 0.02) [3]. Another retrospective series documented an OS of 15.6 months in 16 patients who received systemic chemotherapy versus 7.7 months in 21 patients who did not receive such treatment [12]. The substantial improvement in OS shown in several retrospective studies is evidence of a clear efficacy of 5-FU-based chemotherapy in the treatment of metastatic small bowel adenocarcinoma. Currently, the regimens used in this regard are 5-FU-leucovorin-oxaliplatin (FOLFOX), 5-FU-leucovorin-irinotecan (FOLFIRI) and capecitabine-oxaliplatin (CAPOX). A more recent retrospective study of 80 patients suggested that platinum-based chemotherapy provided a better overall response rate (ORR) at 46% and a longer median progression-free survival (PFS) of 8.7 months compared to other regimens (16%, p = 0.01 and 3.9 months; p ≤ 0.01). Notwithstanding, the median OS was not significantly different (14.8 vs 12 months; p = 0.10) [13]. These findings are further supported by the retrospective multicenter Association des Gastroenterologues Oncologues (AGEO) study of 93 patients comparing 5-fluorouracil-leucovorin (LV5FU2), FOLFOX, FOLFIRI and LV5FU2-cisplatin. In this study, although not statistically significant due to lack of power, the FOLFOX-treated group had a median OS time of 17.8 months compared with LV5FU2 (13.5 months), FOLFIRI (10.6 months) and LV5FU2-cisplatin (4.8 months) [6]. A prospective Phase II study of capecitabine and oxaliplatin in 30 patients with advanced adenocarcinoma of the small bowel and papilla of Vater showed an ORR of 50% with a median time to progression of 11.3 months and median OS of 20.4 months [14]. In a prospective study of 33 patients from China who received FOLFOX treatment for advanced small bowel adenocarcinoma, the objective response rate was 48.5%, with a median time to progression of 7.8 months and a median OS of 15.2 months [15]. In the Phase II NCCTG trial of 23 patients, capecitabine- oxaliplatin-irinotecan (CAPOXIRI) regimen showed an ORR of 39%, a time to progression of 8.7 months and a median OS of 12.7 months [16]. Based on the aforementioned studies, we believe that FOLFOX or CAPOX should be used as a first-line treatment of metastatic small bowel adenocarcinoma. However, we realize the limitations of our recommendations, given the small sample size and retrospective nature of most of these studies.

Table 1. Studies evaluating the role of systemic chemotherapy in metastatic small bowel adenocarcinoma.

Chemotherapy agent/combination	Sample size (n)	Study design	Results and comments	Ref.
5FU+Cisplatin 5FU monotherapy Non-5FU-based	29 41 10 Total = 80	Retrospective	Best results seen with 5FU+cisplatin: ORR = 46% PFS = 8.7 months	[13]
LV5FU2 FOLFOX FOLFIRI LV5FU2+cisplatin	10 48 19 16 Total = 93	Retrospective	Best results seen with FOLFOX: OS = 17.8 months	[6]
CAPOX	30	Prospective	CAPOX achieved ORR = 50% TTP = 11.3 months OS = 20.4 months	[14]
FOLFOX	33	Prospective	ORR = 48.5% TTP = 7.8 months OS = 15.2 months	[15]
CAPOXIRI	23	Prospective	ORR = 39% TTP = 8.7 months OS = 12.7 months	[16]
FOLFIRI	28	Retrospective	ORR = 20% PFS = 3.2 months OS = 10.5 months	[17]
5FU+Irinotecan (second-line)	8	Retrospective	PFS = 5 months	[18]
5FU monotherapy 5FU+cisplatin FOLFOX FOLFIRI Other agents and combinatins	60 17 22 11 22 Total = 132	Retrospective	Best results seen with FOLFOX: ORR = 42% PFS = 8.2 months OS = 22.2 months	[20]

5FU: 5-Fluorouracil; CAPOX: Capecitabine + oxalipatin; CAPOXIRI: Capecitabine+oxaliplatin+irinotecan; FOLFIRI: 5-Fluorouracil-leucovorin-irinotecan; FOLFOX: 5-Fluorouracil-leucovorin-oxalipatin; LV5FU2: 5FU+ leucovorin; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival; TTP: Time to progression.

In these circumstances, FOLFIRI would only be logical as a second-line therapy. Indeed, this is supported by the results of the multicenter AGEO retrospective study of 28 patients who received this regimen and achieved an ORR of 20%, with a median PFS of 3.2 months and an OS of 10.5 months [17]. An older retrospective study of eight patients showed that 5-FU + irinotecan as second-line chemotherapy resulted in disease stabilization in four patients with a median PFS of 5 months [18]. Patients with advanced small bowel adenocarcinoma who are older, frail, intolerant to or experience significant side effects of oxaliplatin or irinotecan should be offered 5-FU or capecitabine alone.

We believe that a major weakness of the published clinical trials is that they lump together patients with small bowel adenocarcinoma and carcinoma of the papilla of Vater. The latter may represent a distinct clinico-pathologic entity, possibly related to hepatobiliary malignancies. A recent study by Chang et al. involving 208 patients with ampulla of Vater adenocarcinoma showed that patients with histomolecular pancreaticobiliary phenotype (CDX2 negative and MUC1 positive) and lymph node metastases had worse outcomes than those with nonpancreaticobiliary (intestinal) carcinoma and no evidence of lymph node involvement [19]. This study supports the theory that ampulla of Vater tumor is a separate histologic and clinical entity and should perhaps be treated differently than other small bowel adenocarcinomas. Furthermore, we believe that advanced cancers originating in the papilla of Vater deserve a randomized clinical trial of cisplatin-gemcitabine, the current standard of care for advanced biliary cancers.

In addition to classic chemotherapy agents, the future of cancer therapeutics relies on new targeted and biologic agents, which is also one of the directions of small bowel cancer research. At present, there is no role for agents such as bevacizumab, regorafenib or EGFR inhibitors in small bowel adenocarcinoma therapy; however, clinical trials are underway [9]. Several trials are currently open including Phase II trial evaluating CAPOX + bevacizumab as first-line treatment in 30 patients with advanced small bowel adenocarcinoma and ampullary cancers (NCT00354887), a Phase II trial evaluating 33 patients with small bowel adenocarcinoma receiving capecitabine/oxaliplatin/irinotecan as first-line treatment (NCT00433550), a Phase II CAPOX + panitumumab as first-line treatment in 20 patients with small bowel adenocarcinoma and ampullary cancers (NCT01202409), a Phase Ib GEMOX (gemcitabine-oxaliplatin) + erlotinib as first-line treatment of duodenal and ampullary cancers in 22 patients (NCT00987766) as well as a Phase II nab-paclitaxel trial as second-line treatment of small bowel adenocarcinoma in 10 patients (NCT01730586) [9].

Studies of molecular profiling showed that small bowel adenocarcinomas harbor losses of 18q and 17p genes. They display similar to their large bowel counterparts rates of microsatellite instability (MSI-high), CpG island methylator phenotype (CIMP+) and KRAS mutations [9]. However, they lack the pivotal APC nonsense mutations seen in colorectal cancers [9]. As we move forward to the next phase of molecular profiling of these malignancies, we may be able to approach this disease more logically, via using novel biologic or targeted therapies with or without traditional chemotherapy agents.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.