Clinical and pathological outcomes of induction chemotherapy before neoadjuvant radiotherapy in locally‐advanced rectal cancer

Abstract Background and Objectives In North America, preoperative combination chemoradiation is the most commonly recommended and utilized approach to locally advanced rectal cancer. There is increasing interest in the use of induction chemotherapy (IC) before radiation and surgery in locally advanced rectal cancer. How widely IC is being used and whether it improves pathologic and oncologic outcomes is unknown. Methods We evaluated clinical stage 2 or 3 rectal cancer patients in the National Cancer Database between 2006 and 2015. We identified predictors of use of IC with multivariable logistic regression and compared survival between groups using Cox proportional hazards regression. Results Among 36 268 patients, IC use increased significantly over time from 5.5% in 2006 to 15.9% in 2015 (P < 0.001). Treatment at a hospital with a high IC rate was an independent predictor of receipt of IC. IC and traditional therapy yielded similar pathologic complete response rates (32.2% vs 30.5%, P = 0.2) and similar 5‐year survival (82.4% vs 81.4%, 0.71). Conclusions Use of IC for locally advanced rectal cancer has increased significantly. The choice of IC seems to be driven more by institutional and regional practice patterns than clinical characteristics and is not associated with improved pathologic or oncologic outcomes.

Adherence to neoadjuvant chemoradiotherapy remains inadequate; however, with significant variation in treatment based on center type, volume, and geographic location. 3 More recently, single-center studies have reported the use of induction chemotherapy (IC) before combination chemotherapy and radiation followed by surgery, 4,5 with the goals of introducing systemic therapy earlier in the course of treatment, and potentially increasing the rate of complete pathologic response. 6 Others have endorsed the delivery of all chemotherapy and radiation before surgery, recognizing that surgical complications preclude adjuvant chemotherapy in up to 34% of patients. 7,8 There is only a small phase 2 randomized trial comparing IC to adjuvant chemotherapy, which did not identify a difference in pathologic complete response or survival between groups. 9 Despite this, the National Comprehensive Cancer Network Guidelines now include IC among endorsed options for treatment of stages 2 and 3 rectal cancer. 10 To date, large scale or randomized studies comparing IC against standard preoperative chemoradiation are lacking. The National Cancer Institute-supported PROSPECT trial randomized patients to standard chemoradiation or IC with the selective omission of preoperative radiation, but outcomes of this trial are still forthcoming. 11 On the one hand, IC might induce the more preoperative response, reducing the likelihood of local failure, and treating occult metastatic disease earlier. On the other hand, delayed surgery might allow local expansion and worsen the likelihood of surgical margin clearance and leave more time for the primary tumor to metastasize.
The real-world outcomes of the IC strategy cannot be assessed without population-based evaluation outside of highly-selected case series. The prevalence of IC use outside of the highly specialized institutions that have reported its use is unknown.
In this study, we used the National Cancer Database (NCDB), which includes data from all American College of Surgeons Commission on Cancer accredited hospitals, accounting for approximately 70% of all cancer patients in treated US hospitals. 12 This population-based cohort offers a realistic epidemiologic assessment of the outcomes of patients with locally advanced rectal cancer nationwide. We used data on timing of chemotherapy, radiation and surgery to classify therapy as either IC before radiation or traditional concurrent chemoradiation before surgery. We sought to understand time trends and patient and provider characteristics associated with the use of IC, and the clinical and pathologic outcomes of IC compared with traditional chemoradiation. Among patients who received radiation and/or chemotherapy as initial course of therapy, we defined two groups of interest using variables available in the NCDB (1) the IC group was defined as patients who received chemotherapy separate from radiation before surgery and (2) traditional therapy was defined as patients who received concurrent chemotherapy and radiation before surgery | 309 chemotherapy and radiation concurrently less than 10 days apart-in fact, a majority of these patients started both on the same day. To further specify the comparison group of traditional chemoradiotherapy followed by surgery, we excluded patients who underwent surgery greater than 22 weeks after chemotherapy and radiation, as these likely represent patients who initially refused surgery, had substantial complications of therapy, or initially pursued nonoperative management.

| Statistical analysis
Descriptive statistics were used to compare characteristics of patients between treatment groups, using χ 2 tests for categorical variables, the Student t test for continuous variables, and analysis of variance for multicategory comparisons of continuous data. We identified independent predictors of receiving IC using multivariable logistic regression, including patient factors (age, race, rectal cancer stage, place of residence, income, type of insurance, and receipt of postoperative chemotherapy) and hospital factors (regional location and facility type) that were significant in the univariate analysis. We categorized the hospital rate of IC into quartiles and included this in the model to account for the role of institutional practice patterns.
We compared overall survival between therapy regimens using multivariable Cox proportional hazard regression, adjusting for the same patient and hospital factors as above, and applying robust standard errors to account for clustering of outcomes within hospitals. All statistical analyses were conducted using STATA version 14 (StataCorp LP, College Station, TX).
Univariable comparisons of hospital characteristics treating rectal cancer patients in the IC or traditional therapy groups is shown in Table 2. Patients receiving IC were more likely to be treated in an Academic/Research Program Hospital (42.4% vs 32.8%, P < 0.001) and more likely to be treated in the Middle Atlantic region (18.6% vs 12.7%, P < 0.001).
In multivariable logistic regression analysis, displayed in Table 3

| DISCUSSION
In this study, we find that, despite the lack of large randomized trials to support IC, there has been a steady annual increase in its use for clinical stages 2 and 3 rectal cancer and that the primary determinant of this use is institutional practice pattern, rather than clinical Atlantic region were also more likely to receive IC. We did not find; however, evidence to support an effect of IC on the likelihood of either complete pathologic response or overall survival. This study utilized data from the NCDB, which is a population-based, nationwide sample, representing the vast majority of treated rectal cancers in US hospitals. Thus, it provides a realistic assessment of national practice patterns beyond just specialty referral centers.
The use of IC is just one of several recent changes in the prevailing treatment approaches for rectal cancer. In general, the trend has been toward more treatment being given before by surgery and then chemotherapy to 308 patients receiving all of their therapy before surgery. 5 The only randomized trial was a phase 2 study from Spain which compared IC to adjuvant in a total of 108 patients and this study did not identify a difference in pathologic complete response (the primary endpoint) or survival between groups despite improved compliance with receipt of planned chemotherapy. 9,21 In summary, the use of IC may achieve one of two goals. First, sensitive tumors will shrink completely before surgery and patients will receive earlier systemic therapy. The second is that many but not all patients receive a survival benefit from FOLFOX 22