The Impact on Survival of Neoadjuvant Treatment Interruptions in Locally Advanced Rectal Cancer Patients

Abstract

The standard oncologic treatment of locally advanced rectal cancer is long-course radio-chemotherapy followed by surgery and adjuvant chemotherapy. This can result in a lengthy total treatment duration, sometimes up to one year from the diagnosis. Interruptions to neoadjuvant treatment can occur for a variety of reasons, forced or unforced. The main purpose of this study is to analyze the survival data of locally advanced rectal cancer patients who received neoadjuvant treatment and to find a cut-off point showing exactly how many days of interruption of neoadjuvant treatment the risk of death or disease relapse increases. We conducted a retrospective study on 299 patients with locally advanced rectal cancer using survival analysis (Kaplan-Meier curve and Cox regression) to determine survival probabilities for overall survival, local control, and disease-free survival. Patients with 0 to 3 days of neoadjuvant therapy interruption had a higher overall survival probability compared to patients with 4 or more days (90.2% compared to 57.9%, p-value < 0.001), hazard ratio 5.89 (p < 0.001). Local control and disease-free survival had a higher probability in patients with 0-2 days of interruption compared to people with 3 or more days (94% vs. 75.4%, and 82.2% vs. 50.5%, respectively, both p-values < 0.001). Patients with tumoral or nodal downstaging experienced fewer days of interruption than patients with no downstage. These findings reinforce the need for radiation oncologists to be well-organized when starting neoadjuvant treatment for rectal cancer, in order to anticipate and prevent potential treatment interruptions and achieve the best therapeutic results.

Keywords: downstage; locally advanced rectal cancer; neoadjuvant radiotherapy; total neoadjuvant treatment; treatment interruptions.

Figure 1

(A) Distribution of patients by radiation dose; (B) distribution of patients by radiotherapy technique; (C) distribution of patients by tumor location; (D) distribution of patients by age; (E) distribution of patients by interruption reason.

Figure 2

(A.1) Overall survival for the whole population; (A.2) DFS for the whole population; (A.3) LC for the whole population; (B.1) overall survival for cTNM stages II and III; (B.2) DFS for cTNM stages II and III; (B.3) local control for cTNM stages II and III; (C.1) overall survival by ypTNM stages; (C.2) DFS by ypTNM stages; (C.3) LC by ypTNM stages.

Figure 3

(A) Overall survival divided by the number of interruption days; (B) local control divided by number of interruption days; (C) disease-free survival divided by number of interruption days; (D) ROC curve for survival; (E) ROC curve for local relapse; (F) ROC curve for disease relapse; (G) overall survival divided by the 3.5 days of interruption cut-off; (H) disease-free survival divided by the 2.5 days of interruption cut-off; (I) local control divided by the 2.5 days of interruption cut-off.

Figure 4

Mann–Whitney tests comparing the distribution of patients with no downstaging versus people with tumoral or nodal downstaging.

Figure 5

(a) HE × 400. Pathological complete response after neoadjuvant therapy, with tumor regression grade score 0 (Modified Ryan Scheme): no residual cancer cells: extensive fibrosis, microcalcifications, foamy histiocytes, and multinucleated giant cells. (b) HE × 400. Residual colorectal adenocarcinoma after neoadjuvant therapy with near complete response (tumor regression grade score 1, according to modified Ryan scheme): an isolated residual group of cancer cells (*), with a preponderance of fibrosis; (c) HE × 400. Residual colorectal adenocarcinoma-G3 after neoadjuvant therapy with no response (tumor regression grade score 3, according to Modified Ryan Scheme: extensive residual groups of cancer cells outgrowing fibrosis. HE-hematoxylin and eosin stain.

Figure 6

(A.1) Overall survival for patients grouped by tumoral downstaging; (A.2) DFS for patients grouped by tumoral downstaging; (A.3) LC for patients grouped by tumoral downstaging; (B.1) overall survival for patients grouped by nodal downstaging; (B.2) DFS for patients grouped by nodal downstaging; (B.3) LC for patients grouped by nodal downstaging.