With versus Without Primary Tumor Radiotherapy in Patients with Unresectable Stage IV Rectal or Rectosigmoid Cancer: A Propensity Score Matching Analysis for Survival

Background: To evaluate the impact of primary tumor radiotherapy on survival in patients with unresectable metastatic rectal or rectosigmoid cancer. Methods: Form September 2008 to September 2017, 350 patients with unresectable metastatic rectal or rectosigmoid cancer were retrospectively reviewed in our center. All patients received at least 4 cycles of chemotherapy, and were divided into two groups according to with primary tumor radiotherapy or without. 163 patients received primary tumor radiotherapy, and the median radiation dose was 56.69Gy(50.4-60). Survival curves were estimated from the Kaplan–Meier procedure to roughly compare survival among two groups. Subsequently, 18-month survival was used as the outcome variable for this study. This study mainly evaluated the impact of primary tumor radiotherapy on survival of these patients through a series of multivariate Cox regression analyses after propensity score matching (PSM). Results: The median follow-up time was 21 months. All 350 patients received a median of 7 cycles of chemotherapy (range 4-12), 163 (46.67%) patients received primary tumor radiotherapy for local symptoms. The Kaplan–Meier survival curves showed a significant overall survival (OS) advantage for primary tumor radiotherapy group to without radiotherapy (20.07 vs 17.33 months; P=0.002). In this study, multivariate Cox regression analysis after adjusted covariates, multivariate Cox regression analysis after PSM, and inverse probability of treatment weighting (IPTW) analysis and propensity score (PS)-adjusted model analysis consistently showed that primary tumor radiotherapy could effectively reduce the risk of death for these patients at 18 months (HR: 0.62, 95% CI 0.40-0.98; HR:0.79, 95% CI:0.93-1.45; HR: 0.70, 95% CI 0.55-0.99 and HR: 0.74, 95% CI:0.59-0.94). Conclusion: Compared with patients with stage IV rectal or rectosigmoid cancer who did not receive primary tumor radiotherapy, received primary tumor radiotherapy reduced the risk of death in these patients. The radical doses59.4Gy/ 33 fractions or 60Gy/ 30 fractions of radiation for primary tumors might be considered for unresectable metastatic rectal or rectosigmoid cancer, not just for relieve symptoms.


Background
In China, the number of newly diagnosed colorectal cancer patient was 376,300 in 2015. Rectal or rectosigmoid cancer accounted for about 50% and 27% of new cases [1][2]. Approximately 25% of colorectal cancer patients present with overt metastases, and an additional 25-35% of patients will develop metastases during the course of their disease [3]. Of which, around 80-90% patients had no chance to conduct a complete surgical removal of all metastatic tumors [3][4]. The prognosis of these patients was extremely poor, and the median survival time of unresectable stage IV rectal cancer was about 5-6 months [5]. At present, systemic chemotherapy is still the preferred treatment for stage IV unresectable colorectal cancer. Radiotherapy or resection of the primary tumor is only recommended for patients with primary tumor progression by the National Comprehensive Cancer Network (NCCN) guideline. These patients usually have obvious local symptoms such as obstruction, bleeding, pain.
Although there is some controversy, most of the studies show that resection of primary tumor without metastasectomy not only relieves pelvic symptoms in patients with metastatic colorectal cancer, but also improves the survival of them [6,7,8]. However, there is few studies exploring whether radiotherapy of primary tumor can also improve the survival of these patients. To provide more meaningful clinical evidence to answer this question,in this study, we retrospectively analyzed 350 patients with stage IV unresectable rectal or rectosigmoid cancer using PSM analyses to explore if there were any survival benefits in patients who received primary tumor radiotherapy.

Methods
We retrospectively reviewed 366 patients who were initially diagnosed with stage IV unresectable rectal or rectosigmoid cancer form September 2008 to September 2017 in our center. All patients received at least 4 cycles of chemotherapy, some of whom had significant local pelvic symptoms  Table 1. Table 1 Comparison of clinical and treatment characteristics between the patients with primary tumor radiation and without.  Table 4). The 10 variables were included in propensity score matching. There were 91 matched patients in each group by 1:1 individual matching without replacement. The matching situation was shown in Fig. 3, the clinicopathological features were presented in Table 3. The primary tumor radiotherapy group still shown lower risk of death than without primary tumor radiotherapy group after propensity score matching (HR:0.79, 95% CI:0.93-1.45; Table 4). The sensitivity analyses using propensity score-based IPTW and PS-adjust model yielded similar results (   Table 3 Clinicopathological features between the two groups after propensity score matching.

Discussion
With the application of oxaliplatin and irinotecan combined with fluorouracil regimen, the survival time of stage IV colorectal cancer ranged from 16 to 20 months [9][10][11]. After entering the era of targeted drugs combined with chemotherapy, the survival time of stage IV colorectal cancer has been significantly improved to 25-35 months [12].
For patients with stage IV colorectal cancer who cannot be cured by radical operation, in general, resection or radiotherapy as a local treatment was used to relieve local obstruction, hemorrhage and pain. More clinical studies focus on the benefits of primary tumor resection alone. Although there are still controversies at present [13,14], most of the existing clinical studies show that the resection of the primary tumor alone can not only reduce the incidence of local complications [15], but also seem to benefit the survival of patients [7,16,17]. However, there are limited data regarding the effect of primary tumor radiotherapy in stage IV unresectable rectal or rectosigmoid cancer, and most of these studies are mainly observing the palliative effect [18][19][20][21]. To our knowledge, there have only been a very few studies to explore the effects of primary tumor radiotherapy on survival of metastatic rectal cancer. For clinical researchers, the main reason is that there are many factors that can affect the survival of patients with stage IV rectal cancer, and that have large individual differences. In retrospective observational studies, conventional multivariate regression analysis is difficult to effectively remove the interference of confounding factors and selection bias on the results, which makes the analysis results lack reliability and consistency. At the same time, it is very difficult to implement such randomized controlled trials,for example, two previous trials(NCT01086618 and NCT01978249) were terminated due to recruitment problems. This study designed a series of analyses based on PSM to minimize the interference of other confounding factors and selection bias on the research results.
In previous clinical studies of primary tumor radiotherapy for metastatic rectal cancer, radiotherapy doses were generally low. Sager et al. reviewed many of studies in which the dose of radiotherapy delivered to primary tumor ranged from 25 to 50 Gy [22]. When the α/β for the tumor was assumed to be 10 Gy for the biologically equivalent dose (BED), the BED of above studies ranged from 37.

Conclusions
In this study, compared with patients with stage IV rectal or rectosigmoid cancer who did not receive primary tumor radiotherapy, received primary tumor radiotherapy reduced the risk of death in these patients for 18 months. The dose pattern of 59.4 Gy in 33 fractions or 60 Gy in 30 fractions was acceptable during concurrent chemotherapy. The radical doses of radiation for primary tumors might be considered for inoperable metastatic rectal or rectosigmoid cancer, not just for relieve symptoms.   The Kaplan-Meier curves for primary tumor radiotherapy and without primary tumor radiotherapy.

Figure 3
Propensity score based on linear model.