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 [9–11]. 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 [18–21]. 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 37.5 to 53.1 Gy. In this study, the radiation dose of the primary tumor was significantly higher than in previous clinical studies. 78% of patients received a radical dose (59.4 Gy in 33 fractions or 60 Gy in 30 fractions), the average radiation dose was 56.69 Gy and the average BED was 67 Gy. As we all know, the higher radiation doses are closely related to better local tumor control.
In this study, Kaplan-Meier survival analysis showed that the median survival times of the primary tumor radiotherapy group and without radiotherapy group were (20.07 ± 8.98) months and (17.33 ± 7.34) months, respectively. This was consistent with previous studies on the stage IV colorectal cancer who only received chemotherapy (median survival was 16 to 20 months), so we decided to use 18-month survival as the outcome variable of this study. Further, in this study, the priori selection of covariates was based on previous studies and the experience of the authors, but also considered the results of univariate analysis. In the subsequent analysis, multivariate Cox regression analysis after adjusted covariates, analysis after PSM, and IPTW analysis and PS-adjusted model analysis which in order to examine the reliability of the results, all analysis consistently showed that primary tumor radiotherapy could effectively reduce the risk of death for these patients at 18 months. In the analysis results of the above different analysis models, although the hazard ratio (HR) value has increased significantly, the nature of reducing the risk of death has not changed, and the range of the confidence interval has gradually narrowed,our results became more conservative and accurate by IPTW and PS-adjusted model analysis. A retrospective observational study similar to this study shows that palliative radiotherapy could improve the survival of metastatic rectal cancer [23]. However, several deficiencies exist in the study. The study did not further analyze the location of the lesion (primary or metastatic) targeted by palliative radiotherapy, nor did it involve the dose. Chemotherapy, as an important factor affecting the survival of metastatic rectal cancer, was not analyzed in this study. These deficiencies have been corrected in this study.
There are still some shortcomings and limitations in this study: (1) The time range of eligible patients included in this retrospective study was from September 2008 to September 2017. During this period, the price of Bevacizumab and Cetuximab in China were expensive and not included in the local health care insurance, patients who can afford it were rare, so this study did not select patients who received Bevacizumab or Cetuximab. The lack of targeted drugs will definitely reduce the survival benefit of patients and may affect the benefits of radiotherapy for primary tumors. (2) Compared with 12 cycles recommended by the guidelines, the median chemotherapy cycle in this study was relatively low, only 7 cycles. Fewer chemotherapy cycles will reduce the therapeutic efficacy of all patients and may have an uncertain impact on the benefits of primary tumor radiotherapy. (3) This study was a real-world study (observational clinical study). There might be some confounding factors outside out clinical cognition and previous literature reports that may affect the accuracy of the research results.