Editor's Note: At the 2024 Annual Meeting of the Shanghai Anti-Cancer Association’s Gastrointestinal Tumor Laparoscopy Committee, Dr. Hongwei Yao from Beijing Friendship Hospital，Capital Medical University delivered an outstanding presentation titled The Value of Long-Course Radiotherapy Combined with PD-1 Inhibitors in Neoadjuvant Therapy for Mid-to-Low Rectal Cancer: Research and Reflections. Following his presentation, Dr. Yao spoke with us in an exclusive interview.Oncology Frontier: Could you explain the unique value of combining long-course radiotherapy with PD-1 inhibitors in neoadjuvant therapy for mid-to-low rectal cancer? What advantages has this treatment strategy shown in clinical practice?
Dr. Hongwei Yao: Since 2020, we’ve been exploring the combination of long-course radiotherapy and PD-1 inhibitors. To substantiate our findings, we used pathological complete response (pCR) as the primary endpoint in our studies. Conducting a multicenter cohort study across seven national centers, we discovered a pCR rate of 40%—significantly higher than the average response rate of around 15% for traditional neoadjuvant chemoradiotherapy at institutions such as Beijing Friendship Hospital.
That said, this study had its limitations. Firstly, it was a phase II study with a small sample size of about 50 patients, among whom 20 achieved disease remission. Building on these findings, we initiated a phase II multi-arm study and are now conducting a nationwide, multicenter phase III study with a larger cohort.
Several leading centers in China are conducting similar research. For instance, Dr. Zhen Zhang from Fudan University Shanghai Cancer Center, Dr. Kaixiong Tao from Union Hospital at Tongji Medical College, and Dr. Tao Zhang from various oncology centers have reported pCR rates ranging from 40% to 50%. Achieving pCR is crucial, as it means zero local recurrence for patients.
For mid-to-low rectal cancer, the key to improving clinical outcomes lies in avoiding unnecessary surgeries and preserving organs. Recent studies focused on organ preservation suggest that achieving pCR offers patients the opportunity to retain their organs, laying the groundwork for subsequent “watch-and-wait” strategies.
Oncology Frontier: While the combination of long-course radiotherapy and PD-1 inhibitors shows great potential in neoadjuvant therapy for mid-to-low rectal cancer, certain challenges remain. What major challenges have you encountered in clinical practice, and what areas should future research prioritize?
Dr. Hongwei Yao: Based on our research and clinical practice over the past four years, two key challenges stand out:
- Managing immune-related toxicities: Combining immunotherapy with radiotherapy inevitably increases the risk of related toxicities. Identifying and mitigating these risks requires collaboration with oncologists and specialists from other disciplines. Unlike the common side effects of traditional chemoradiotherapy, such as bone marrow suppression, gastrointestinal reactions, and leukopenia, immunotherapy presents unique toxicities known as immune-related adverse events (irAEs). These include immune-related colitis, pneumonitis, hepatitis, thyroiditis, hyperthyroidism, hypothyroidism, and even myocarditis. Approximately 4.6% of patients at our center experienced grade 3 or higher severe irAEs. Addressing these adverse events demands multidisciplinary teamwork, timely recognition, and appropriate intervention to optimize treatment efficacy and improve patient outcomes.
- Assessing disease response: Evaluating disease response after neoadjuvant chemoradiotherapy combined with immunotherapy is particularly challenging. Even before immunotherapy became part of the regimen, determining clinical remission after neoadjuvant chemoradiotherapy was difficult. Data shows that the concordance rate between clinical and pathological remission is only about 70% at major centers like Fudan University Shanghai Cancer Center, and as low as 50–60% at general centers.
While some patients achieve clinical remission, conventional diagnostic tools often fail to detect residual disease. The real challenge lies in identifying patients with excellent response who can avoid rectal surgery and its associated long-term functional impairments. Currently, clinical assessments rely on traditional methods such as digital rectal exams, pathological biopsies via endoscopy, MRI, tumor markers, and sometimes PET-CT. We are also developing biomarkers to predict immunotherapy outcomes, although these efforts are still in the exploratory stage.
Our research on the tumor microenvironment has revealed distinct differences between patients who achieve complete remission and those who do not. For example, the presence of tumor-associated macrophages and PD-1-positive T cells differs significantly between responders and non-responders. In the future, we aim to use biomarkers and biopsy techniques to identify patients with favorable local immune environments.
Oncology Frontier: In the context of long-course radiotherapy combined with PD-1 inhibitors, how can we better tailor individualized treatment plans for patients?
Dr. Hongwei Yao: In China, multidisciplinary treatment (MDT) teams for colorectal cancer include specialists in oncology surgery, medical oncology, radiotherapy, pathology, and imaging. Over the past five years, MDT teams have spearheaded numerous studies, exploring the combination of long- and short-course radiotherapy with PD-1 inhibitors and chemotherapy. Centers in Beijing, Shanghai, Guangzhou, Wuhan, and Chengdu have led multicenter clinical trials, yielding promising results and opening new doors for treating mid-to-low rectal cancer.
We can boldly predict that, in the future, approximately 50% of patients with mid-to-low rectal cancer may not require radical surgery. Avoiding surgery eliminates the long-term functional issues associated with it. However, the challenge lies in precisely identifying which patients will benefit most from this approach.
By testing for mismatch repair (MMR) status, we can identify patients who are sensitive to immunotherapy. These patients show a disease remission rate as high as 90%. Therefore, all colorectal cancer patients should undergo MMR or microsatellite instability (MSI) testing at diagnosis.
For the remaining 95% of patients who are not sensitive to immunotherapy—especially those with proficient MMR (pMMR) or microsatellite-stable (MSS) tumors—precision treatment is necessary. Treatment strategies should be tailored based on tumor stage and the distance of the tumor from the anus. These strategies may include long- or short-course radiotherapy combined with different chemotherapy regimens and, selectively, PD-1 inhibitors.
The growing body of evidence supporting immunotherapy is reflected in numerous high-quality, large-scale studies. Over the next three to five years, these findings are likely to be incorporated into clinical guidelines, particularly for traditionally immunotherapy-insensitive populations such as pMMR or MSS patients.
