A new pharmacological approach to gastrointestinal cancer at high risk of relapse based on maintenance of the cytostatic effect

Abstract

In metastatic colorectal and other locally advanced gastrointestinal cancers, the mechanisms of tumor growth and/or immune escape by residual cancer cells after curative resection often provoke tumor recurrence. Current adjuvant therapy is based on pharmacological administration up to 6-8 months after surgery. We hypothesized that the long-term, cytostatic action from repeated post-adjuvant administration of 5-fluorouracil (FU)-leucovorin (LV) cycles, as a result of the downregulation of the above-mentioned cellular mechanisms, could halt tumor progression. An active prospective cohort, including 19 patients (study group) at high risk of relapse, was considered. All patients received repeated post-adjuvant administration of 5-FU-LV cycles for up to 52-60 months following curative surgery (total cumulative dose of about 90 g and mean follow-up of 70.6 ± 49.7 months). The 5-year disease-free interval (DFS) and overall survival (OS) were 80.4 ± 10.2% and 87.1 ± 8.6%, respectively, which is very different from the recent literature that has reported 5-year DFS and OS values of 31.8% and 40.1%, respectively. These findings suggest that this new pharmacological approach based on the long-term maintenance of a cytostatic effect with 5-FU-LV can produce a relevant improvement in the outcome of this population.

Additional 5-FU-LV significantly increases survival in gastrointestinal cancer

“…The number of relapses and deaths that occurred within the five years following curative resection and the cumulative five-year DFS and OS rates for all three groups are shown in Table 3. The cumulative 5-year DFS and OS rates in the 21 matched and in the 28 unmatched controls were similar to those expected and previously reported (11). So far, no relapse and only one death due to metastatic disease occurred after five years (control n. 1, matched controls).…”

“…As to adjuvant CT, it has to be considered that in most locally advanced GI cancers and in colorectal cancer after curative resection of liver metastases, no recommended standard adjuvant therapy does exist, because no certain DFS and OS benefit has been reported (21)(22)(23)(24)(25)(26). In this study, the five-year DFS and OS of our matched and unmatched control groups were in line with those reported in the literature (11). A significant difference was also confirmed when all matched and unmatched control patients were used as a control group.…”

“…Therefore, the working hypothesis was to observe in the entire studied population a significant decrease in relapses and a prolonged OS. In 19 recently reported of these patients tested with this new pharmacological approach, 5-year DFS and OS were significantly better than in similar patients as expected from literature data (11). In the present report, we updated the study group and collected data from all similar G.I.…”

“…cancer. In this exploratory study, we have hypothesized that in patients at high risk of relapse the post-adjuvant intermittent and long-term administration of 5-FU-LV may reduce the activities of residual cancer cells and halt tumor progression (11). Therefore, the working hypothesis was to observe in the entire studied population a significant decrease in relapses and a prolonged OS.…”

Tumour growth and immune evasion as targets for a new strategy in advanced cancer

“…In a pilot study conducted by a group (Nicolini et al 2010) in patients with GI cancers who were apparently disease free after primary surgery and had a high risk of relapse due to residual undetectable metastases, an almost double 5-year disease-free survival (DFS; 80.4%) and OS (87.1%) was reported compared with the expected. In this study, starting from the first year after conventional adjuvant chemotherapy till the fifth year, patients received 2-3 cycles of additional adjuvant chemotherapy using infusional 5-fluorouracil (FU) plus leucovorin.…”