Editor’s Note:
The 2023 European Society for Medical Oncology (ESMO) Annual Meeting was held in Madrid, Spain, from October 20th to 24th. Professor Tao Zhang and Professor Kaixiong Tao from Tongji Medical College of Huazhong University of Science and Technology and their team conducted a randomized Phase III trial, the UNION study (Abstract Number: LBA25), entitled “Neoadjuvant Short-Course Radiotherapy Followed by Cetuximab in Combination with CAPOX vs. Long-Course Sequential Chemotherapy in the Treatment of Locally Advanced Rectal Cancer.” The study was selected for presentation as a proffered paper at the ESMO conference. “Oncology Frontier” interviewed Professor Tao Zhang and Professor Kaixiong Tao , and they interpreted the UNION study from both internal medicine and surgery perspectives, sharing their insights and thoughts on perioperative treatment for rectal cancer. This issue compiles the relevant content for readers.
Interview with Professor Tao Zhang
- Oncology Frontier: The randomized Phase III UNION study, which investigates neoadjuvant short-course radiotherapy followed by cetuximab in combination with CAPOX for the treatment of rectal cancer, was successfully selected for presentation as a proffered paper at the 2023 ESMO conference. Could you please discuss the current diagnosis and treatment status of rectal cancer and the background for conducting the UNION study?
- Professor Tao Zhang
The main endpoints of the UNION study in China, which was announced at this year’s ESMO conference, showed favorable results. Over the years, neoadjuvant treatments for rectal cancer have included long-course radiotherapy and short-course radiotherapy. In North America, neoadjuvant long-course chemotherapy is primarily used, while in Europe, short-course radiotherapy is followed by delayed surgical treatment with chemotherapy during the interval to improve the rate of pathological complete response. In fact, both of these different preoperative radiotherapy approaches have been recommended in major clinical guidelines, including CSCO, NCCN, and ESMO guidelines. However, it seems that the efficacy of both neoadjuvant long-course synchronous chemotherapy and short-course radiotherapy followed by chemotherapy for treating mid-to-lower rectal cancer has reached a plateau, and immunotherapy may offer more opportunities for patients.
We were inspired by the VOLTAGE-A study, which used long-course chemotherapy in combination with immunotherapy for MSS populations, achieving a pCR rate of 30%. With the advent of immunotherapy, it is unclear whether the majority of MSS patients can also benefit from it, as MSI-H patients do. Radiotherapy, especially high-dose radiotherapy, has a synergistic effect with immunotherapy. Therefore, we considered whether short-course radiotherapy followed by chemotherapy and immunotherapy could increase the rate of pathological complete response (pCR). In 2019, with the support of Jiangsu Hengrui Medicine Co., Ltd., we designed a Phase II study to investigate the neoadjuvant treatment of rectal cancer with short-course radiotherapy in combination with cetuximab and CAPOX chemotherapy. Patients received short-course radiotherapy followed by two cycles of cetuximab and CAPOX before undergoing total mesorectal excision (TME). We were delighted to find that this new treatment approach achieved a pCR rate of 48.1%. Subsequently, with the support of Jiangsu Hengrui Medicine Co., Ltd., our center led a nationwide, prospective, multicenter, randomized Phase III UNION study in collaboration with nine excellent research units. After two years of work, the study has achieved its primary endpoints.
2. Oncology Frontier: Could you please introduce the study design of this Phase III UNION study and the challenges or issues you encountered during its implementation?
- Professor Tao Zhang
The UNION study is a prospective, multicenter, randomized Phase III study led by our center and conducted by a total of nine centers nationwide. In the end, 231 patients were enrolled and randomly divided into two groups: the study group with 113 cases and the control group with 118 cases. The study group received short-course radiotherapy followed by two cycles of cetuximab in combination with CAPOX, followed by total mesorectal excision (TME), and then received six cycles of cetuximab in combination with CAPOX postoperatively, with cetuximab maintenance therapy afterward. The total treatment duration did not exceed one year. The control group received long-course synchronous chemotherapy followed by two cycles of CAPOX, followed by TME, and then received six cycles of CAPOX treatment postoperatively.
First, the biggest challenge during the implementation of this study was that it started in July 2021, right in the midst of the COVID-19 pandemic. We were concerned that this might affect patient enrollment. However, thanks to the concerted efforts of the teams at various centers, we were able to smoothly complete enrollment. As of March this year, 231 patients were enrolled in 20 months. This was achieved through the collective dedication of our researchers.
Second, during the lockdown period, we were very concerned about the execution rate of the study protocol, as unexpected events could occur during lockdown, and a high dropout rate would impact the quality of the study. However, with the collective efforts of our research teams, the execution rate of the study protocol was excellent, and there were not many protocol violations or dropouts, with a dropout rate of less than 10%, which greatly ensured the quality of our study.
Third, during the study, we encountered a professional challenge. In classic preoperative chemotherapy, the clinical complete response (cCR) rate and the pathological complete response (pCR) rate have good consistency. However, with the addition of immunotherapeutic drugs, we were surprised to find a significant disparity between the clinical imaging cCR rate and the final pCR rate. Current methods for assessing cCR rates do not reflect the ultimate therapeutic efficacy very well. We have also conducted some exploratory work in this area, hoping to achieve more research results in the future that align clinical imaging assessment of cCR with pCR in terms of consistency.
03. Oncology Frontier: Could you please introduce the main results of the UNION study, which investigated short-course radiotherapy followed by cetuximab in combination with CAPOX as neoadjuvant treatment for locally advanced rectal cancer patients? This includes efficacy and safety data and the value of the study results for current clinical practice.
- Professor Tao Zhang
The efficacy data showed that the primary endpoint, the pCR rate, in the study group was 39.8%, compared to 15.3% in the control group (P < 0.001). Therefore, short-course radiotherapy followed by cetuximab in combination with CAPOX significantly improved the rate of pathological complete response compared to long-course synchronous CAPOX chemotherapy. In terms of tumor regression rate, the median tumor regression rate was 98% in the study group and 85% in the control group. Regarding the sphincter preservation rate, the study group achieved a sphincter preservation rate of 94.2%, while the control group had a rate of 89.9%. Key secondary endpoints include 3-year disease-free survival (DFS) and overall survival (OS), which will require further follow-up.
Safety data showed that there were no significant differences between the two groups in terms of all adverse events (AE) and treatment-related AEs. This new treatment approach did not increase the occurrence of more side effects compared to the classic chemotherapy approach. In terms of surgery-related complications, there were also no significant differences between the two groups.
Why did we conduct this study? Colorectal cancer is the second most common malignant tumor in men, and in China, the proportion of rectal cancer is higher than in the West. About half of Chinese mid-to-lower rectal cancer patients have tumors located within 5 cm of the anal verge. For such patients, we need to ensure their survival while preserving their anal function and improving their quality of life. Everyone is considering how to increase the rate of pathological complete response, providing an opportunity for watch-and-wait (W&W) management for mid-to-lower rectal cancer patients and preserving their anal function. The high pCR rate achieved in the UNION study has significant clinical value. If we can help more patients achieve pathological complete response, not only can they avoid the pain of surgery, but they also have more opportunities for sphincter preservation, retaining normal anal function, and improving their quality of life. This aligns with the higher expectations of patients and healthcare professionals for the treatment of this disease. In the baseline analysis of patients, nearly half of them had tumors located within 5 cm of the anal verge, and nearly 80% were stage III patients. We used to think that this treatment approach might work well for relatively early-stage patients, such as T3N0-1 patients. Later, we found that it also has good effects on relatively advanced T4, and even N2 patients, with an improved pCR rate compared to previous studies.
04. Oncology Frontier: This year’s ESMO conference presented the latest advances in the preoperative treatment of locally advanced rectal cancer. Could you discuss the current diagnosis and treatment status of rectal cancer, and the background for conducting the UNION study, drawing from your clinical and research experience?
- Professor Tao Zhang
In recent years, there have been significant changes in the incidence and treatment modalities of rectal cancer. International and national clinical guidelines recommend neoadjuvant treatment for locally advanced mid-to-low rectal cancer, which involves using treatments such as radiotherapy, chemotherapy, and immunotherapy before surgical treatment. The goal is to reduce the tumor size, stage, and local recurrence rate, thereby improving sphincter preservation and long-term survival. Neoadjuvant treatment for locally advanced mid-to-low rectal cancer can include short-course radiotherapy in combination with chemotherapy or long-course radiotherapy in combination with chemotherapy.
In recent years, immunotherapy has gained widespread attention for its success in treating various advanced cancers and has been recommended as a first-line treatment in multiple indications. In clinical practice, we’ve observed that preoperative immunotherapy, short-course radiotherapy, and chemotherapy, such as the CAPOX regimen, have synergistic effects and can effectively kill cancer cells, achieving tumor downstaging. Therefore, our center initiated a Phase II study on the neoadjuvant treatment of locally advanced rectal cancer using short-course radiotherapy followed by cetuximab in combination with CAPOX. The results showed a pCR rate of 48.1%, meaning that nearly half of the patients treated with this regimen had complete tumor cell eradication. Subsequently, our center led a nationwide, prospective, multicenter, Phase III UNION study involving nine centers to investigate the neoadjuvant treatment of locally advanced rectal cancer with short-course radiotherapy followed by cetuximab in combination with CAPOX. The aim was to validate the favorable efficacy and safety observed in the Phase II study through this Phase III clinical research.
05. Oncology Frontier: Can you discuss the challenges and issues encountered during the process of conducting the Phase III UNION study?
- Professor Kaixiong Tao
In mid-2020, we obtained the efficacy and safety data from the Phase II clinical study. At the end of 2020, we began preparations for the Phase III study. The preparatory phase included extensive communication among multiple centers, ethical and scientific evaluations. In July 2021, we officially launched the nationwide, multicenter, randomized, prospective Phase III UNION study. Patient recruitment continued until March 2023. Over the past one to two years, the world has been grappling with the COVID-19 pandemic, leading to lockdowns and restrictions in various regions. This had an impact on patient recruitment and their ability to seek medical care, as many patients couldn’t access healthcare facilities promptly. However, through persistent efforts, we managed to complete patient recruitment in approximately 20 months. I want to express my sincere appreciation to all the researchers involved in this study, especially the principal investigators at each center. Conducting this clinical study required collaboration from multidisciplinary teams. I also want to extend my gratitude to the patients and their families for their understanding and support.
06. Oncology Frontier: Does neoadjuvant treatment with short-course radiotherapy in combination with cetuximab and CAPOX have a significant impact on surgery (such as surgical approach and safety)? As a surgeon, could you share the value of the study’s results for current clinical practice and the changes it has brought to multidisciplinary collaboration in the treatment of locally advanced rectal cancer?
- Professor Kaixiong Tao
As a surgeon, I’m highly concerned about the safety of surgical procedures and the occurrence of postoperative complications. Neoadjuvant treatments can have varying impacts on surgery, with patients who have undergone neoadjuvant therapy typically experiencing fewer factors that affect surgery compared to those who haven’t received any neoadjuvant treatments.
The UNION study compared the neoadjuvant treatment of locally advanced rectal cancer with short-course radiotherapy in combination with cetuximab and CAPOX to long-course radiotherapy in combination with CAPOX. Based on observed clinical safety data, both the study group and the control group had a certain proportion of hematologic toxicity, gastrointestinal reactions, and other adverse effects during the neoadjuvant treatment phase. However, there were no significant differences between the two groups. There were no significant differences in tissue edema and the difficulty of tissue anatomy between the two groups. On the contrary, we observed a lower proportion of preventive ostomies in the study group, indicating a potential benefit from short-course radiotherapy, although this trend did not reach statistical significance. Overall, there were no significant differences in preoperative adverse effects, factors affecting surgical difficulty, or postoperative complications such as anastomotic bleeding and fistula between the study group and the control group. The existing data from the UNION study suggests that both the classic long-course radiotherapy and short-course radiotherapy in combination with cetuximab and CAPOX are acceptable options for mid-to-low rectal cancer patients who require neoadjuvant treatment. The side effects, surgical difficulty, and postoperative complications associated with these treatments are acceptable. This reflects one of the advantages of our clinical research.
During the UNION study, when patients experienced complications, we discussed and addressed them through multidisciplinary collaboration. Through this Phase III clinical study, all surgeons involved in the treatment of rectal cancer gained a deeper understanding of the concept of multidisciplinary collaboration. This concept will be more widely promoted in clinical practice and represents an excellent model for the diagnosis and treatment of cancer.
Collaborating Centers and PI
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology : Tao Zhang/Kaixiong Tao
Peking Union Medical College Hospital : Yi Xiao
Fujian Medical University Union Hospital : Pan Chi
Hebei University Affiliated Hospital : Aimin Zhang
Fujian Provincial Cancer Hospital : Junxin Wu
Renmin Hospital of Wuhan University : Ximing Xu
Zhongshan Hospital, Xiamen University : Xingfeng Qiu
Second Hospital of Zhejiang University School of Medicine : Ying Yuan
First Hospital of China Medical University : Zhenning Wang /Xiujuan Qu
“Original abstract”
LBA25 – Neoadjuvant short-course radiotherapy followed by camrelizumab plus chemotherapy versus long-course chemoradiotherapy followed by chemotherapy in locally advanced rectal cancer: A randomized phase III trial (UNION)
Background
Based on the results of pre-clinical research and our phase II study, we conducted a randomized, multicenter, open-label phase III study to compare the efficacy and safety of short-course radiotherapy (SCRT) followed by immunochemotherapy versus long-course chemoradiotherapy (LCRT) followed by chemotherapy for perioperative treatment of locally advanced rectal cancer (LARC).
Methods
Patients (pts) with T3-4 or N+ rectal adenocarcinoma, where the lower edge of the tumor was ≤ 10 cm from the anal verge, were randomly assigned to either Arm A or B in a 1:1 ratio. Stratification was based on clinical T stage (≤ T3 vs. T4) and N stage (N0 vs. N+), and pts received SCRT or LCRT, followed by 2 cycles of camrelizumab (CAM) + CAPOX or CAPOX, respectively. Total mesorectal excision (TME) was performed subsequently, with an additional 6 cycles of CAM + CAPOX followed by CAM for up to 1 year in Arm A, and 6 cycles of CAPOX in Arm B. Primary endpoint was the independent review committee (IRC)-assessed pCR rate (ypT0N0). Secondary endpoints tested hierarchically were 3-year EFS rate and OS.
Results
Between July 2021 and March 2023, 231 pts were randomly assigned to Arm A (n=113) and Arm B (n=118). In Arm A, 112 pts received SCRT, 107 completed neoadjuvant therapy, and 104 underwent TME. In Arm B, 115 pts received LCRT, 109 completed neoadjuvant therapy, and 99 underwent TME. The IRC-assessed pCR rate in the ITT populations was significantly improved in Arm A (39.8% [95% CI 30.7-49.5]) versus Arm B (15.3% [95% CI 9.3-23.0]), with an odds ratio of 3.7 ([95% CI 2.0-6.9], p<0.001), meeting the primary endpoint. Subgroup analysis showed consistently positive results across all subgroups. In the surgical population, the R0 resection rate was 96.2% in Arm A and 97.0% in Arm B. Postoperative complications occurred in 38.1% of pts in Arm A versus 40.8% in Arm B. Grade ≥ 3 TRAEs were observed in 29.2% of pts in Arm A and 27.2% in Arm B throughout the treatment. Long-term survival outcomes are currently being monitored.
Conclusions
SCRT followed by CAM and chemotherapy demonstrated a superior pCR rate with acceptable tolerance compared to LCRT followed by chemotherapy for LARC.
Clinical trial identification
NCT04928807.
