Immunologic Consequences of Sequencing Cancer Radiotherapy and Surgery

Abstract

Purpose: Early-stage cancers are routinely treated with surgery followed by radiotherapy (SR). Radiotherapy before surgery (RS) has been widely ignored for some cancers. We evaluate overall survival (OS) and disease-free survival (DFS) with SR and RS for different cancer types and simulate the plausibility of RS- and SR-induced antitumor immunity contributing to outcomes.

Materials and methods: We analyzed a SEER data set of early-stage cancers treated with SR or RS. OS and DFS were calculated for cancers with sufficient numbers for statistical power (cancers of lung and bronchus, esophagus, rectum, cervix uteri, corpus uteri, and breast). We simulated the immunologic consequences of SR, RS, and radiotherapy alone in a mathematical model of tumor-immune interactions.

Results: RS improved OS for cancers with low 20-year survival rates (lung: hazard ratio [HR], 0.88; P = .046) and improved DFS for cancers with higher survival (breast: HR = 0.64; P < .001). For rectal cancer, with intermediate 20-year survival, RS improved both OS (HR = 0.89; P = .006) and DFS (HR = 0.86; P = .04). Model simulations suggested that RS could increase OS by eliminating cancer for a broader range of model parameters and radiotherapy-induced antitumor immunity compared with SR for selected parameter combinations. This could create an immune memory that may explain increased DFS after RS for certain cancers.

Conclusion: Study results suggest plausibility that radiation to the bulk of the tumor could induce a more robust immune response and better harness the synergy of radiotherapy and antitumor immunity than postsurgical radiation to the tumor bed. This exploratory study provides motivation for prospective evaluation of immune activation of RS versus SR in controlled clinical studies.

FIG 1.

(A) SEER inclusion/exclusion. (B) Kaplan-Meier 20-year survival.

FIG 2.

Hazard ratios (HRs; with 95% CIs, P values, and linear least squares regression lines weighted by the inverses of site-specific CIs) for (A) disease-free survival (DFS) and (B) overall survival (OS) after preoperative (neoadjuvant) RT (RS) compared with postoperative (adjuvant) RT (SR). HRs were adjusted for age, sex, year of diagnosis, histology, type of surgery, type of applied radiation, and tumor size. Equation describes the trend line, and coefficients were tested for significant difference from 0 using t test. (*) P < .05. (†) P < .001. RT, radiotherapy

FIG 3.

(A) Model-predicted treatment outcomes of radiotherapy (RT) alone, RT after surgical resection (SR), and RT before surgical resection (RS) without RT-induced immunity (ie, q = 0.0 day⁻¹ in Equation 2) in a cohort of virtual patients with different combinations of pretreatment tumor size, tumor growth rate (r), and immune recruitment rate (f) in response to tumor burden. Radiation is delivered to a total dose of 50 Gy in 25 daily fractions at 2 Gy per day, 5 days per week. Tumor control (TC) by treatment (blue) and progressive disease (PD; red) refer to tumor eradication and escape after treatment, respectively. (B) Time evolution of tumor and effector T cells corresponding to the location marked by stars in panel A.

FIG 4.

(A) Model-predicted treatment outcomes of radiotherapy (RT) alone, RT after surgical resection (SR), and RT before surgical resection (RS) for tumors of 10⁸ viable cancer cells pretreatment and increasing strength of RT-induced immunostimulation (q, day⁻¹ in Equation 2) in a cohort of virtual patients with different combinations of tumor growth rate (r) and immune recruitment rate (f) in response to tumor burden. Radiation is delivered to a total dose of 50 Gy in 25 daily fractions at 2 Gy per day, 5 days per week. Tumor control (TC) by treatment (blue) and progressive disease (PD; red) refer to tumor eradication and escape after treatment, respectively. (B) Time evolution of tumor and effector T cells corresponding to the locations marked by diamonds, triangles, and stars in panel A.

FIG 5.

Comparison of immune recruitment and treatment outcomes for tumors of 10⁸ viable cancer cells pretreatment with tumor growth rate (r) between 0.1 and 0.4 day⁻¹ and immune recruitment rate (f) in response to tumor burden between 0.1 and 0.3 day⁻¹. (A) Recruitment of effector T cells to the tumor bed as a result of radiotherapy (RT) –induced immune responses by surgery followed by RT (SR). (B) Recruitment of effector T cells to the tumor bed as a result of RT-induced immune responses by RT followed by surgery (RS). Recruitment of effector T cells after both SR and RS is estimated by the integral of the term qD in Equation 2, with q = 4.5 × 10⁻¹ day⁻¹. Arrows point to the parameter combinations that yield tumor control (TC) by SR and RS (c.f. Fig 4A). (C) Proportion of parameter space controlled for SR (25 daily fractions at 2 Gy per day, 5 days per week; blue line) compared with RS with gradually increasing number of fractionations. (D) Proportion of parameter space controlled for SR (25 daily fractions at 2 Gy per day, 5 days per week; blue line) compared with RT alone with increasing number of fractionations. Parameters are 0.1 ≤ r ≤ 0.4 day⁻¹ and 0.1 ≤ f ≤ 0.3 day⁻¹. Different strengths of RT-induced immunostimulation are color coded (q, day⁻¹ in Equation 2).

FIG A1.

Model-predicted treatment outcomes of radiotherapy (RT) alone, RT after surgical resection (SR), and RT before surgical resection (RS) for tumors of 10⁸ viable cancer cells pretreatment and increasing number of treatment fractions in a cohort of virtual patients with different combinations of tumor growth rate (r) and immune recruitment rate (f) in response to tumor burden. Radiation is delivered to total doses of 50, 60, and 70 Gy in 25, 30, and 35 daily fractions at 2 Gy per day, 5 days per week. Tumor control (TC) by treatment (blue) and progressive disease (PD; red) refer to tumor eradication and escape after treatment, respectively. For all simulations, we set RT-induced antitumor immunity to q = 4.5 × 10⁻¹ day⁻¹.

FIG A2.

Kaplan-Meier 20-year disease-free survival (DFS) curves for each of the considered cancer sites, with 95% CIs.

FIG A3.

Results of analysis using multivariable Cox proportional hazard model performed after propensity score matching of the adjuvant and neoadjuvant radiotherapy (RT) cohorts for each cancer site separately. Hazard ratios (HRs; with 95% CIs, P values, and trend lines obtained using linear least squares weighted by the inverses of site-specific CI lengths) for (A) disease-free survival (DFS) and (B) overall survival (OS) after preoperative (neoadjuvant) radiation (RS) compared with postoperative adjuvant radiation (SR). HRs were adjusted for age, sex, year of diagnosis, histology, type of surgery, type of applied radiation, and tumor size. Equation describes the trend line, and coefficients were tested for significant difference from 0 using t test. (*) P < .05. (†) P < .001.

FIG A4.

Proportion of parameter space controlled by radiotherapy (RT) alone, RT after surgical resection (SR), and RT before surgical resection (RS) for different values of (A) the lysis rate of tumor cells killed by RT (n) and (B) the T cell–cancer interactions constant (a; Equations 1 to 3). Radiation is delivered to a total dose of 50 Gy in 25 daily fractions at 2 Gy per day, 5 days per week. For all simulations, we set RT-induced antitumor immunity to q = 4.5 × 10⁻¹ day⁻¹ and tumors of 10⁸ viable cancer cells pretreatment.

FIG A5.

Model-predicted treatment outcomes of radiotherapy (RT) alone, RT after surgical resection (SR), and RT before surgical resection (RS) for tumors of 10⁸ viable cancer cells pretreatment and increasing surviving fractions of tumor cells at 2 Gy (SF₂) in a cohort of virtual patients with different combinations of tumor growth rate (r) and immune recruitment rate (f) in response to tumor burden. Radiation is delivered to a total dose of 50 Gy in 25 daily fractions at 2 Gy per day, 5 days per week. Tumor control (TC) by treatment (blue) and progressive disease (PD; red) refer to tumor eradication and escape after treatment, respectively. For all simulations, we set RT-induced antitumor immunity to q = 4.5 × 10⁻¹ day⁻¹.

FIG A6.

Model-predicted treatment outcomes of radiotherapy (RT) alone, RT after surgical resection (SR), and RT before surgical resection (RS) for tumors of 10⁸ viable cancer cells pretreatment and increasing surviving fractions of effector cells at 2 Gy (SF₂) in a cohort of virtual patients with different combinations of tumor growth rate (r) and immune recruitment rate (f) in response to tumor burden. Radiation is delivered to a total dose of 50 Gy in 25 daily fractions at 2 Gy per day, 5 days per week. Tumor control (TC) by treatment (blue) and progressive disease (PD; red) refer to tumor eradication and escape after treatment, respectively. For all simulations, we set RT-induced antitumor immunity to q = 4.5 × 10⁻¹ day⁻¹.