In the current era of finding an accurate treatment for rectal cancer, insights into the effects of preoperative treatment, and determination of the best form of therapy is very important. This study showed no difference in DFS, OS, and pCR rates between the two different modes of preoperative treatments. In a randomized study by Bujko et al 6, T3/4 stage patients receiving chemoradiation (50·4 Gy in 28 fractions of 1·8 Gy, bolus 5-fluorouracil, and leucovorin) were compared with patients who underwent radiation therapy (5×5 Gy), and the study reported no significant difference in the 4-year OS (66% vs. 67%, respectively) and DFS (58.4% vs. 55.6%, respectively). These findings were consistent with the results of this study.
Stockholm III trial 9 was the first to compare three different radiotherapy regimens (SC with immediate surgery, SC with delayed surgery, and LC with delayed surgery). However, the trial revealed that there was no significant difference in OS and DFS among the three groups. Besides, the pCR rate in the SC group with delayed surgery (10%) was superior to the other two groups 10. In the present study, the pCR rate in the SC group (25%) was found to be better compared to the LC group (18.1%), and both were higher than 10%. This may be because the SC group received more preoperative chemotherapy. A previous meta-analysis found that LC presented a better pCR rate compared with the SC without chemotherapy, meaning that chemotherapy may enhance the efficacy of preoperative treatment 11. Another randomized phase III study by Bujko et al. 12 compared patients receiving radiotherapy (5 × 5 Gy) and three cycles of FOLFOX4 with those receiving 50.4 Gy in 28 fractions combined with two 5-day cycles of bolus 5-Fu 325 mg/ m2/day and leucovorin 20 mg/m2/day during the first and fifth week of irradiation along with five infusions of oxaliplatin 50 mg/m2 once weekly. This study found that the pCR, DFS and OS in the two groups were, 16% versus 12% (P=0.17), 53% versus 52% (P=0.85), and 73% versus 65% (P=0.046), respectively, thus confirming the importance of adequate chemotherapy. In the present study, we found better nodal downstaging in the SC group. However, this is not consistent with the results of the study by Brandon et al. 13, which found that the LC group were more likely to have nodal (25% vs 19%) downstaging, and pCR (15% vs 6%) compared with the SC group (all P< 0.05). SC itself has a similar biological effective dose as LC 14. The large fractions used in SC can be more efficient in inducing both the innate and adaptive anti-tumor immunity, and eventually increase the biologic effects of concomitant and consolidation chemotherapy 15. This results from the release of antigens due to the breakdown of tumoral cells, and the presentation of the antigens to T cells 16. This difference may also be associated with the higher preoperative chemotherapy in the SC group in this study and SC with delayed surgery is also reported to have a satisfactory downstaging effect 17. A matched pair analysis also observed that patients treated with SC and sequential FOLFOX Chemotherapy had improved rates of downstaging compared to the matched LC cohort 18. This was precisely because early chemotherapy is likely to improve the overall therapeutic effect, hence complete neoadjuvant therapy has been proposed. There are two main proposed treatment modes: first chemoradiotherapy, and then consolidation chemotherapy, or the reverse order, induction chemotherapy first, and then chemoradiotherapy. In a multicentre, phase 2 trial by Julio et al. 19, 292 patients with stage II or III rectal cancer were divided into four groups and received zero, two, four, or six cycles of consolidation chemotherapy after preoperative chemoradiotherapy. After a median follow-up of 59 months, patients who received consolidation chemotherapy were found to have improved DFS (P<0.05), and there were differences in survival between groups in patients who received at least one cycle of FOLFOX. In another phase III study 20 (STELLAR trial) in China, comparing short-course radiotherapy followed by chemotherapy with long-course chemoradiotherapy in LARC, the results showed that pCR rates in the experimental and control group were 18.6% vs. 5.4% (P=0.029), respectively. These findings were consistent with the pCR rates reported in this study (18.1%-25%).
The potential economic benefit cannot be ignored during the formulation of treatment. Using the micro-cost calculation method, Hanly et al. reported that SC is cheaper than LC 21. Another study 22 analyzed the cost-effectiveness of immediate surgery after SC and LC with delayed surgery and showed that SC was the most cost-effective strategy. However, LC was also found to be a cost-effective approach for patients with distal tumors. Wang et al. 23 considered the economic benefits of both short-term and long-term radiotherapy after chemotherapy. Although the total cost of SC was much higher than that of LC ($78,937 and $38,140 respectively), the final result that was calculated through quality-adjusted life months (QALMs), found that SC was more cost-effective.
The National Comprehensive Cancer Network (NCCN) guidelines recommend SC as an acceptable alternative to LC except for patients with T4 stage rectal cancer 24. Additionally, the American Society for Radiation Oncology (ASTRO) guidelines state that for patients with a high risk of circumferential resection margin positive or difficulty in R0 resection, LC should be used, otherwise both radiotherapy methods can be used 25. Both SC and LC are recommended options for neoadjuvant treatment of LARC, however, the decision to choose one or the other is based on several considerations, including (1) LC is favored when a patient is at risk of surgical resection margin or when tumors are distal and/or bulky and would benefit from downstaging, (2) SC followed by consolidation chemotherapy may be the most promising order for total neoadjuvant therapy (3) LC is the preferred approach when nonoperative management is being considered as it increases the chances of a complete clinical response compared with SC, (4) SC may be used in elderly and frail patients with comorbid conditions, such as heart failure since it is better tolerated than LC due to lower toxicity, and (5) SC may be used in countries with low health-care budgets or medical centers with long waiting lists because it is less expensive and more convenient.
There are still limitations to this study. Firstly, the imbalance in the number of patients receiving SC and LC may cause deviations in the results. More cases need to be included in future studies for more convincing results. Another limitation is the short follow-up time, thus evaluating long-term outcomes is uncertain. Therefore, follow-up time needs to be further extended. Then the limitations of preoperative staging should be taken into account. A meta-analysis on the diagnostic accuracy of MRI in rectal cancer patients showed that the specificities of MRI for the T category and lymph node involvement were only 75% and 71% 26. However, these limitations would equally affect the two groups in this study and the results would not be offset. Lastly, although we confirmed the importance of chemotherapy in the neoadjuvant therapy in locally advanced rectal cancer patients, due to the retrospective nature of this study, it was difficult to confirm which chemotherapy regimen or cycle number would be more beneficial. Further related research needs to be carried out in the future.