In terms of incidence, colorectal cancer (CRC) is the third most common malignant tumor worldwide, with around 2.3 million cases. Its fatality rate has surpassed liver cancer to take the second position, skyrocketing to approximately 0.9 million deaths (1). As such, CRC is a serious threat to human health. About half of all CRC cases are of rectal cancer (RC), which is most common among individuals over 45 and has a far greater prevalence in men (2). In addition, China is predicted to have an enormous number of cases of CRC in 2022. According to the most recent data (3), China is estimated to have as many as 517,000 CRC cases (ranked second only to lung cancer) and 240,000 fatalities (ranked fourth), which is a concerning number.

About 60–70% of patients with RC develop locally advanced rectal cancer (LARC, which means TNM stage II-III RC), which is also staged as T3/T4 and/or including regional lymph node metastases (T3-4N0M0 or TanyN+M0); however, there is no universally accepted definition for it. For LARC, there currently exist two established preoperative neoadjuvant regimens: short-course radiotherapy (SCRT) with immediate surgery (widely applied in northern Europe) and conventional long-course chemoradiotherapy (LCCRT) based on fluorouracil with surgery 6–8 weeks later (accepted by the United States and southern Europe) (4). The efficacy and safety of the two strategies have already been demonstrated in prior studies (5–7), including decreasing tumor local recurrence and improving survival. However, in terms of pathologic complete remission (pCR) and potential micrometastasis (higher distant disease recurrence), SCRT appears to be less effective compared with LCCRT (8). Hence, SCRT is more suitable for low-to-moderate risk LARC (e.g., T3N0M0 and T1-2N1M0 without extramural vascular invasion, compromised mesorectal fascia, or positive circumferential resection margin) (2, 4). Moreover, the Stockholm III and Polish II trials (5, 9) have fortunately shown that advancing intensive systemic chemotherapy in the interim between SCRT and surgery has successfully increased pCR and tumor downstaging rates in comparison to LCCRT, which can also shorten the duration of treatment, reduce financial toxicity, and improve patients’ adherence to subsequent treatment.

This systematic review and meta-analysis aims to provide a deeper understanding of short-course radiotherapy followed by consolidation chemotherapy (SCRT/CCT) regimens by summarizing the available data about total neoadjuvant therapy (TNT) based on SCRT/CCT for LARC. It also investigates the efficacy of the included randomized controlled trials (RCTs) in terms of disease-free survival (DFS), overall survival (OS), pCR rate, surgical R0 resection rate, and other metrics.

Due to consolidation chemotherapy and prolonged surgery, the SCRT/CCT arm showed non-inferiority in tumor-downstaging status and had an enhanced pCR rate, according to our meta-analysis. Consequently, a trend of a lower distant recurrence rate was also noted. This is because SCRT may be more conducive to activating the systemic immune system and promoting local T-cell activation to maximize anti-tumor efficacy. However, these advantages did not translate into benefits for survival. The two arms performed comparably in terms of survival outcomes (OS and DFS events) but also surgical indicators (such as surgery R0 resection rate, sphincter preservation rate, and surgery complication rate). Oncologists should be made aware of the fact that the SCRT/CCT group experienced an increase in acute grade 3–4 adverse events, despite the fact that the pCR rate was increasing in that group.

Prior research (16, 17) has demonstrated improved OS and DFS in patients who achieve pCR following neoadjuvant therapy for LARC. PCR has been considered to be a highly valuable signal for evaluating the effectiveness of short-term treatment and predicting long-term prognosis, even though it cannot entirely replace OS or DFS. The results of this meta-analysis showed that the pCR rate in the experimental group was significantly higher than that in the control group [RR = 1.67, 95% CI (1.36, 2.04), P<0.001]. The administration of systemic chemotherapy in the experimental group and the extension of the time between chemoradiotherapy and surgery may be the reasons for the rise in the pCR rate. In conventional neoadjuvant therapy, the disadvantage of applying SCRT combined with immediate surgery for LARC patients is that the interval is too short and the possibility of clinical tumor complete remission is lost in most instances. The results of the Stockholm III trial (5) showed that if surgery was delayed for 4–8 weeks after SCRT, the pCR rate increased significantly to 11.8%, while the pCR rate in the group with immediate surgery after SCRT was only 2.1%. According to previous studies (18–20), the pCR rate after delayed surgery with SCRT, although increased, was not higher than that with LCCRT; therefore, simply extending the interval between SCRT and surgery is not an optimal substitute for conventional LCCRT for the treatment of LARC.

A prospective phase II trial conducted by Garcia-Aguilar et al. (21) compared the effect of SCRT followed by an additional 6 cycles of mFOLFOX6 with surgery in the treatment of LARC on tumor regression. The tumor regression rate improved significantly with increasing cycles of chemotherapy, with a 25% pCR rate in patients who were added 2 cycles of mFOLFOX6 and a 38% pCR rate in patients who were added 6 cycles of mFOLFOX6, which suggested that tumors may shrink if systemic chemotherapy is added to the interval between SCRT and surgery. Hence, more and more RCTs are looking at the feasibility and safety of consolidation or induction chemotherapy. This meta-analysis's improved pCR rate indicated that SCRT plus consolidation chemotherapy (≥ 4 cycles) could be a feasible treatment option for LARC with organ retention needs as well. This study also fully confirmed the hypothesis that the SCRT/CCT regimen would provide similar long-term survival outcomes compared to the LCCRT regimen. Moreover, the results of our meta-analysis indicated that the experimental group’s sphincter preservation rate was comparable to the control group’s, which suggests that more LARC patients may be able to achieve organ preservation, minimize the cost of treatment, and improve their quality of life by choosing the SCRT/CCT scheme. Most importantly, some patients who have experienced clinical complete remission as a result of TNT based on SCRT/CCT may be able to avoid surgery in favor of the “watch-and-wait” strategy (22, 23).

We can’t be entirely positive. Acute grade 3 or higher adverse events were more common in the test group, according to the meta-analysis’s findings, and the difference was statistically significant [RR = 1.94, 95% CI (1.64, 2.28), P<0.001]. The enhanced acute side effects of preoperative systemic chemotherapy could be the cause of this outcome. Similarly, preoperative mFOLFOX-6 consolidation chemotherapy was reported in some studies to improve tumor remission rates and DFS; however, there was a corresponding rise in the incidence of acute toxicity (21, 24). According to the Thavaneswaran et al. meta-analysis study (25), acute grade 3 or higher adverse events were more frequent in the SCRT/CCT group, which is consistent with the results of our study. This meta-analysis showed a higher incidence of acute grade 3-4 adverse events in the SCRT/CCT group, while the overall surgical complications, such as the common anastomotic fistula and incisional infections, were not significantly different between the two groups.

There was no statistically significant difference in the distant metastasis rate between the trial and control groups. We found that distant metastatic occurrences were managed in the SCRT/CCT arm, which is in accordance with the results of the most recent RAPIDO study update (26). To investigate the efficacy of the TNT strategy and to more precisely interpret existing data, longer follow-up and homogeneous clinical trials may be required. Similar to the results of some large clinical trials, including the Polish II trial (9) in Poland, the RAPIDO trial (12) in the Netherlands, and the STELLAR trial (14) in China, our meta-analysis’s outcomes also showed no statistically significant difference in OS and DFS between the two groups, but the statistics undoubtedly indicated a trend toward better OS and DFS in the experimental group. The findings should be interpreted cautiously, nevertheless, as there was some moderate heterogeneity in the OS investigation. The larger clinical trials are required to support more trustworthy conclusions about OS and DFS benefits.

The results of this meta-analysis revealed no discernible difference between the two groups in terms of the R0 resection rate and tumor downstaging rate. According to Park et al. (27), peripheral margin-negative patients had a better 5-year DFS among those who did undergo preoperative chemoradiotherapy (CRT) (88.9% vs. 55.5%), the same as not receiving preoperative CRT (82.8% vs. 54.7%). Positive postoperative pathologic margins also tended to indicate a poor prognosis. In the same way, a study found that individuals with postoperative pathologic stage ypT0-2 were more likely than those with ypT3-4 to benefit from postoperative adjuvant chemotherapy (28). Although the results of this meta-analysis showed no statistically significant difference, the trial arm showed a slight trend toward tumor-downstaging benefits [RR = 0.99, 95% CI (0.85, 1.15), P = 0.92]. Furthermore, we discovered that treatment compliance was higher among patients in the SCRT group. This might be because SCRT, which is divided into 5 fractions, requires a shorter treatment time than LCCRT. In addition to being more affordable and convenient, SCRT also minimizes treatment-related economic toxicity and shortens the number of days that LARC patients must stay in the hospital, particularly in China, where radiotherapy resources are relatively limited.

Unfortunately, since the above RCTs did not include local recurrence rate thoroughly, it was not examined in our meta-study. Indeed, given the low locoregional recurrence rate reported by the LARCT-US study (29) and the combined results of the Polish and STELLAR trials (9, 14), SCRT/CRT should be regarded as unquestionably effective, even though the increased locoregional recurrence rate following longer follow-up in the RAPIDO trial is still unclear. In my opinion, there were a number of factors that were worth taking into account. First of all, by employing the 5 × 5 Gy SCRT [a biological dose equivalent to 2 Gy per fraction from 31 Gy (for α/β = 10) to 36 Gy (for α/β = 5), which is significantly lower than the LCCRT arm] along with consolidation chemo, the experimental group postponed surgery for 40 weeks, and tumor fibrosis ultimately made surgery more difficult and then increased LRR. Secondly, the RAPIDO trial did not conduct a centralized evaluation of radiation plans, which may lead to inadequate dose coverage of the planned target volume and intended recurrences. At last, the RAPIDO trial failed to reach its main goal because a significant percentage of LARC in the experimental arm had high-risk features, which raised the LRR and may have also been caused by inappropriate SCRT.

Therefore, treatment for LARC cannot be generalized; we need to incorporate high-risk factors such as the presence of T4 disease, threatened mesorectal fascia, extramural vascular invasion, lateral or extramesorectal lymph node metastasis, N2, less than 5 cm from the anal verge, and circumferential resection margin positivity, which are all important stratification factors for treatment selections and inform the design of subsequent clinical studies. Likewise, genetic mutations and dMMR status may affect treatment efficacy. We also agree that for LARC patients with high-risk features for local recurrence rate, LCCRT may be preferred due to the poor bioequivalent dose of SCRT, given the results of the RAPIDO trial (30–33). Therefore, in future studies, we need to screen out these high-risk populations suitable for the LCCRT regimen. However, at present, due to the lack of high-level evidence, our meta-study provides important reference options for LARC, especially in healthcare resource-constrained regions.

Several limitations of the present meta-analysis must be taken into consideration. Firstly, only 6 RCTs were included, which means that the number of tumor patients involved was relatively small; secondly, surgery for LARC may ultimately present uneven treatment results because the tumor characteristics were not exactly the same and high spatiotemporal heterogeneity in each study remained; thirdly, surgical ability and proficiency from global healthcare organizations may lead to distinct outcomes; fourth, the completion of adjuvant chemotherapy, the cycles and regimens of consolidation chemotherapy, and the surgical intervals all varied, even in RCTs, which may be the cause of the outcome errors. Eventually, we anticipate that further large-sample and multicenter trials, as well as longer follow-up data in the aforesaid RCTs, will be available in the future to address the aforementioned issues and offer more convincing proof supporting the SCRT/CCT therapy option for LARC patients.

Last but not least, it’s critical to specify at the beginning of treatment whether the sufferer’s objective is pursuing organ preservation by a “watch-and-wait strategy” for the reason that there has now existed more data supporting LCCRT for LARC patients being evaluated for non-surgical management (34). In this regard, the University of Stanford also provides important therapeutic references regarding balancing risk factors for local versus distant recurrence (35). Besides, the ongoing ACO/ARO/AIO-18 trial, which randomly assigns patients to TNT regimens of SCRT versus LCCRT followed by chemotherapy, has been anticipated to provide much-needed clarification on this choice.

Although there may be a larger chance of acute grade 3-4 adverse events, the SCRT/CCT scheme offers patients with LARC a higher pCR rate and an equivalent survival prognosis when compared to LCCRT (34–36). Thus, as a neoadjuvant alternative therapy option for LARC, our RCTs-based meta-analysis study shows that SCRT/CCT is safe and effective, which not only decreases treatment time costs but also increases patients’ compliance to subsequent treatment and facilitates organ retention. The SCRT/CCT regimen deserves to be further utilized, especially in China and economically deprived areas.