Prevention of Colon Cancer Recurrence From Minimal Residual Disease: Computer Optimized Dose Schedules of Intermittent Apoptotic Adjuvant Therapy

Abstract

Purpose: Adjuvant chemotherapy is used after surgery for stages II and III colorectal cancer to reduce recurrence. Nevertheless, recurrence may occur years later with the emergence of initially undetected minimal residual disease (MRD). Attempts to reduce recurrence by increasing the dose intensity and increasing the time of adjuvant therapy have been limited by the adverse effects of the recommended cytotoxic agents. The goals of this study were to suggest an alternative to the recommended cytotoxic agents and to determine optimal adjuvant therapy dose schedules that would reduce the percentage of recurrence at 5 years while retaining colon crypt function.

Methods: A total of 84,400 dose schedules with different duration, interval between doses, and intensity of treatment were simulated with a high-performance computer. Simulated treatments used the drug sulindac, which had previously been used in primary prevention. With appropriate dose schedules, it can induce apoptosis at the crypt lumen surface while retaining crypt function. We used a computer model of cell dynamics in colon crypts that had been calibrated with measurements of human biopsy specimens. Proliferating mutant cells were assumed to emerge from MRD within crypts. Simulated outcomes included the recurrence percentage at 5 years and the retention of crypt function.

Results: Optimal dose schedules were determined for adjuvant treatment of MRD that reduced the percentage of recurrence at 5 years of stages I, II, and III colon cancer to zero.

Conclusion: A new adjuvant therapy for colon cancer based upon optimum dose schedules of intermittent apoptotic treatment may prevent the recurrence of colon cancer from MRD and avoid the adverse effects of cytotoxic treatments.

FIG 1.

Simulated recurrence as a function of time. The simulated 5-year recurrence percentage for stages I, II, and III are 4.8, 11.5, and 32.8 years, respectively. These reproduce the clinically observed recurrences at 5 years. Numerical values for the clinically observed recurrences, the simulated recurrences, and the corresponding probabilities of emergence for each stage are given in Table 1.

FIG 2.

Simulated dose schedules for (A) stage I, (B) stage II, and (C) stage III that were successful in removing all mutants while retaining stable crypt function for 50 years. For each stage, a total of 28,800 different dose schedules were simulated. The number of successful dose schedules for stages I, II, and III were 189, 97, and 46, respectively. Each dot represents 1 successful dose schedule with a specific duration of dose, interval between doses, and intensity of treatment. The color of each dot indicates the accumulated dose in 50 years. Numerical data are provided in the Excel file available at https://doi.org/doi:10.7282/t3-bdd6-df16.

FIG 3.

Comparison of recurrences of different adjuvant therapies for stage II colon cancer. No therapy is the same as that shown in Figure 1. Suboptimal intermittent therapy was simulated with dose schedules of duration of 3, interval of 24, and treatment of 1.4. Suboptimal intermittent therapy reduces recurrence, but 4% of crypts collapse. Optimal intermittent therapy was simulated with dose schedules of duration of 1, interval of 36, and treatment of 2.0. Optimal intermittent therapy of stage II prevents recurrence for 50 years with no crypt collapse. Optimal intermittent therapies for stages I and III, with appropriate dose schedules listed in Table 2, also prevent recurrence for 50 years.

FIG 4.

Mean recurrence percentage at 5 years and 95% CIs (horizontal bars) for stages I, II, and III. Clinical values for no adjuvant therapy and for adjuvant therapy were recalculated from all risk factor categories for each stage reported in Table 2. Values for simulated therapy are listed in Table 2.