Locally advanced gastrointestinal cancers: moving forward in the neoadjuvant setting

Shrinking tumours before surgery has proven to facilitate complete resection and reduce the risk of local and systemic recurrence in many solid tumours. Whilst neoadjuvant chemotherapy is now a well-established strategy for treating some gastrointestinal tumours such as gastric (Ann Oncol. 2016 Sep;27(suppl 5):v38-v49), oesophageal (Lancet 359:1727-1733, 2002) and gastroesophageal cancers (N Engl J Med. 2006 Jul 6;355(1):11-20), for other digestive malignancies evidence from studies is promising, although not yet practice changing.

For instance, the phase III FOxTROT trial showed that neoadjuvant chemotherapy may be an option for some patients with operable localised colon cancer, and mature results published earlier this year reported a reduction in residual and recurrent cancer within 2 years with three cycles of neoadjuvant chemotherapy with FOLFOX (fluorouracil, leucovorin and oxaliplatin) prior to surgery and adjuvant chemotherapy compared to upfront surgery and postoperative chemotherapy (J Clin Oncol. 2023 Mar 10;41(8):1541-1552). In patients with locally advanced rectal cancer, 7-year results from the phase III PRODIGE 23 study demonstrated that neoadjuvant chemotherapy with FOLFIRINOX (leucovorin, fluorouracil, irinotecan and oxaliplatin) followed by chemoradiotherapy, surgery and adjuvant chemotherapy improve all survival endpoints compared to standard care (J Clin Oncol. 2023;41, LBA3504-LBA3504).

Is neoadjuvant treatment strategy taking the scene in the treatment of localised gastrointestinal tumours?

“There is no doubt that the neoadjuvant strategy is a very hot topic in gastrointestinal cancer research, and that the choice of the appropriate treatment should be guided by the molecular features of tumours,” says Prof. Michel Ducreux, Head of the Gastrointestinal Oncology Unit and Gastrointestinal Oncology Tumor Board at Gustave Roussy, Villejuif, France, Scientific Co-Chair of the ESMO Gastrointestinal Cancers Congress 2024 (Munich, 26-29 June).

Mismatch repair (MMR) testing plays a key role in this setting, and the impressive pathological response achieved with neoadjuvant immunotherapy in patients with MMR deficient (dMMR) non-metastatic colon cancer in the NICHE-2 trial show that patient selection is critical to achieve good outcomes. “Preoperative chemotherapy is not indicated for this subgroup of patients, and the major question is now to understand what to do after neoadjuvant immunotherapy when there is a complete pathological response, whether to perform standard treatment with surgery or adopting a watch-and-wait approach.”

Negative trials in pancreatic cancer

Earlier this year, results from the NORPACT-1 study showing that adjuvant FOLFIRINOX has no additional benefit compared to upfront surgery in patients with resectable pancreatic ductal adenocarcinoma, add up to the limited high-level evidence supporting neoadjuvant therapy for pancreatic tumours. Currently, the treatment of these malignancies relies on surgery and adjuvant chemotherapy, which has been enriched in the last decade with the incorporation of a triple combination strategy. However, only about 20% of patients are eligible to upfront pancreatectomy, which remains an extremely challenging surgery with high complication rates and a negative impact on quality of life for patients (Pancreas. 2020 Mar; 49(3): 393–407).

Neoadjuvant strategies thus represent an option to convert locally advanced, unresectable tumours to resectable status for some patients. “Despite evidence is not yet conclusive to establish a neoadjuvant approach in pancreatic cancer, preoperative treatment is today recommended in case of borderline resectable disease, for which surgical resection implies some additional technical difficulties and risks,” explains Prof. Teresa Macarulla, Head of Upper Gastrointestinal Cancer Translational Research Laboratory and the Upper Gastrointestinal and Endocrine Tumors Unit at the Vall d’Hebron Institute of Oncology (VHIO) and Hospital.

Recommendations from the ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up of pancreatic cancer (Ann Oncol. 2023;34(11):987-1002) are based on the outcomes of some studies reporting that induction treatment for borderline resectable pancreatic cancer provides benefit for increasing the R0 resection rate and allows identification of patients most likely to benefit from surgical strategies (Br J Surg. 2018; 105: 946-958; J Clin Oncol. 2022 Apr 10;40(11):1220-1230). “However, whether chemotherapy and/or chemoradiotherapy is the most appropriate treatment is yet to be assessed,” continues Macarulla, who is co-chair of the ESMO Gastrointestinal Cancers Congress 2024 with Ducreux and Prof. Eric Van Cutsem, University of Leuven, Belgium. “Another crucial issue we still need to address is when to administer chemotherapy to those patients who have a completely resectable pancreatic cancer, i.e., before or after surgery, or as perioperative care, and some interesting trials such as the ALLIANCE A021806 and the PREOPANC-3 are now ongoing to provide an answer,” continues Macarulla.

Regarding the new promises in the treatment landscape, Macarulla brings attention to cancer vaccines. “We have some preliminary data which are encouraging, but for the moment vaccines for pancreatic cancer remain an option in the research setting,” she concludes. “However, I believe they have the potential to change the clinical scenario, also in the neoadjuvant setting.”