Abstract
BACKGROUND:
Total neoadjuvant therapy is the recommended modality for patients with locally advanced rectal carcinoma and those whose lesions are <5 cm from the anal verge. The optimal integration of total neoadjuvant therapy remains unclear.
OBJECTIVE:
This study aims to evaluate the efficacy of short-course radiotherapy integrated with immunochemotherapy and long-course chemoradiotherapy plus chemotherapy as modalities of total neoadjuvant therapy.
DESIGN:
Patients diagnosed with rectal carcinoma who received radiotherapy integrated in total neoadjuvant therapy from January 2021 to January 2025 at the First Affiliated Hospital of Zhengzhou University were reviewed. Kaplan-Meier survival analysis was used for survival analysis.
SETTINGS:
This study was a retrospective study conducted at the First Affiliated Hospital of Zhengzhou University.
PATIENTS:
There were 128 patients enrolled in the short-course radiotherapy integrated with immunochemotherapy group and 64 in the long-course chemoradiotherapy plus chemotherapy group.
MAIN OUTCOME MEASURES:
The primary end point was pathological complete response. The secondary end points were the rate of sphincter preservation, disease-free survival, and overall survival.
RESULTS:
The short-course radiotherapy integrated with the immunochemotherapy group had a significantly higher pathological complete response rate than the long-course chemoradiotherapy group (42.2% vs 15.6%, p = 0.001). With a median follow-up of 42.3 months (95% CI, 40.538–43.990), the median disease-free survival was not reached in the short-course group but was 28.3 months in the long-course group (p = 0.02; HR 0.46; 95% CI, 0.205–1.040), respectively. The median overall survival was not reached in either group (p = 0.02; HR 0.33; 95% CI, 0.118–0.910). The rate of sphincter preservation was 75.8% versus 65.6% (p = 0.138).
LIMITATIONS:
Biases resulted from the retrospective nature of this study. The sample sizes of the 2 groups were 128 and 64, resulting in a 2:1 allocation ratio, which may decrease statistical power.
CONCLUSIONS:
The integration of short-course radiotherapy plus immunochemotherapy gives a higher pathological complete response rate than traditional long-course chemoradiotherapy in the modality of total neoadjuvant therapy. The former integration presents a trend of dominance in long-term survival. See Video Abstract.
LA RADIOTERAPIA DE CORTA DURACIÓN INTEGRADA CON INMUNOQUIMIOTERAPIA PRODUCE UNA MAYOR TASA DE RESPUESTA PATOLÓGICA COMPLETA EN COMPARACIÓN CON LA QUIMIORRADIACIÓN DE LARGA DURACIÓN COMBINADA CON QUIMIOTERAPIA EN EL TRATAMIENTO NEOADYUVANTE TOTAL DEL CARCINOMA RECTAL LOCALMENTE AVANZADO EN LA PRÁCTICA CLÍNICA HABITUAL: UN ESTUDIO RETROSPECTIVO
ANTECEDENTES:
La terapia neoadyuvante total es la modalidad recomendada para pacientes con carcinoma rectal localmente avanzado y aquellos cuyas lesiones se encuentran a menos de 5 centímetros del margen anal. La integración óptima de la terapia neoadyuvante total aún no está clara.
OBJETIVO:
Este estudio tiene como objetivo evaluar la eficacia de la radioterapia de corta duración integrada con inmunoquimioterapia y la quimiorradiación de larga duración más quimioterapia como modalidades de terapia neoadyuvante total.
DISEÑO:
Se revisaron los casos de pacientes diagnosticados con carcinoma rectal que recibieron radioterapia integrada en la terapia neoadyuvante total entre enero de 2021 y enero de 2025 en el Primer Hospital Afiliado de la Universidad de Zhengzhou. Se utilizó el análisis de supervivencia de Kaplan-Meier.
CONTEXTO:
Este estudio fue un estudio retrospectivo realizado en el Primer Hospital Afiliado de la Universidad de Zhengzhou.
PACIENTES:
Se incluyeron 128 pacientes en el grupo de radioterapia de corta duración combinada con inmunoquimioterapia, y 64 pacientes en el grupo de quimiorradiación de larga duración combinada con quimioterapia.
PRINCIPALES MEDIDAS DE RESULTADO:
El criterio de valoración principal fue la respuesta patológica completa. Los criterios de valoración secundarios fueron la tasa de preservación del esfínter, la supervivencia libre de enfermedad y la supervivencia global.
RESULTADOS:
El grupo de radioterapia de corta duración combinada con inmunoquimioterapia presentó una tasa de respuesta patológica completa significativamente mayor que el grupo de quimiorradiación de larga duración (42,2% frente a 15,6%, p = 0,001). Con un seguimiento medio de 42,3 meses (IC del 95%: 40,538-43,990), la mediana de supervivencia libre de enfermedad no se alcanzó frente a 28,3 meses (p = 0,02; razón de riesgo = 0,46; IC del 95%: 0,205-1,040), respectivamente. La mediana de supervivencia global no se alcanzó (p = 0,02; razón de riesgo = 0,33; IC del 95%: 0,118-0,910). La tasa de preservación del esfínter fue del 75,8% frente al 65,6% (p = 0,138), respectivamente.
LIMITACIONES:
Sesgos derivados de la naturaleza retrospectiva de este estudio. El tamaño de la muestra de los dos grupos fue de 128 y 64, lo que resultó en una proporción de asignación de 2:1, lo que podría disminuir la potencia estadística.
CONCLUSIÓN:
La combinación de radioterapia de corta duración e inmunoterapia ofrece una mayor tasa de respuesta patológica completa en comparación con la quimiorradiación tradicional de larga duración en la modalidad de terapia neoadyuvante total. Esta combinación presenta una tendencia de superioridad en la supervivencia a largo plazo. (AI-generated translation)
Keywords: Immune checkpoint inhibitors, Locally advanced rectal carcinoma, Long-course radiotherapy, Short-course radiotherapy
Video Abstract
Video Abstract.
Total neoadjuvant therapy (TNT) has revolutionized the treatment of patients with locally advanced rectal carcinoma (LARC) and those with patients who have difficulty with anus preservation. TNT refers to neoadjuvant chemoradiation therapy followed by total mesorectal excision.1 This strategy helps to reduce the rate of local recurrence and improve the rate of organ preservation. The 2 main modalities of TNT are traditional long-course chemoradiotherapy and the novel short-course radiotherapy. These 2 modalities have their own strengths and weaknesses,2–4 making modality selection a pivotal issue in clinical decision-making. However, the recommended modality for TNT and the guidelines for choosing between the 2 modalities remain uncertain.5–7 Therefore, researchers have shown an unremitting interest in exploring the optimal modality of TNT for LARC.
The application of short-course radiotherapy began with a trial conducted by a Swedish group,8 and the 10-year follow-up established its long-term benefit compared with traditional long-course radiotherapy.9 Subsequent studies reported the efficacy of short-course radiotherapy and its noninferiority to long-course chemoradiotherapy.10,11 In 2006, Bujko et al reported that the long-course chemoradiotherapy exhibited a better strength in tumor down-staging.12 The rise of immune checkpoint inhibitors (ICIs) changed the landscape of antitumor strategy, including the treatment strategy for LARC, which motivates the innovation for the modality of TNT for LARC.13 The mode of short-course radiotherapy may synergistically work with ICIs to activate the microenvironment. Stereotactic radiotherapy induced tumor cell death, produced tumor antigens that increased immunogenicity, and generated the remote effects (an abscopal effect of radiotherapy).14,15 Increasing the dose per fraction effectively inhibited the DNA exonuclease Trex1 and subsequently activated the cGAS-STING pathway that led to antitumor function.16 Based on the theory, researchers have launched clinical trials, including TORCH and UNION.17,18 These trials focused on the short-term efficacy, feasibility, and safety of the mode of short-course radiotherapy with immunotherapy but did not directly compare it with traditional long-course chemotherapy. We noticed that a certain number of patients had previously received short-course radiotherapy combined with immunochemotherapy as the modality of TNT. Thus, the aim of this study was to investigate the efficacy of short-course radiotherapy integrated with immunochemotherapy (SCRT) versus long-course chemoradiotherapy integrated with chemotherapy (LCRT) as the mode of TNT in the real world. Data based on real-world clinical management will provide practical information and pave the way for the design of further prospective studies in the era of ICIs.
MATERIALS AND METHODS
Patients
Based on the theory that short-course radiotherapy can synergistically work with ICIs, we assumed that the rate of pathological complete response (pCR) in the SCRT group (50%) would be higher than in the LCRT group (20%), with an increase of 30%. We calculated that the sample sizes should be 76 and 38, with a ratio of at least 2:1.
Patients who were diagnosed with rectal carcinoma and received radiotherapy for preoperation therapy between January 1, 2021, and January 1, 2025, at the First Affiliated Hospital of Zhengzhou University were reviewed (Fig. 1). The inclusion criteria were 1) provided informed consent; 2) age 18 to 70 years; 3) pathologically confirmed rectal carcinoma; 4) stage II or III (American Joint Committee on Cancer, eighth edition),19 or lesion <5 cm from the anal verge; 5) no prior rectal cancer treatment; 6) surgically eligible; 7) Eastern Cooperative Oncology Group scale 0 to 1; and 8) adequate organ function. The exclusion criteria were 1) other active malignancies within 5 years; 2) distant metastases; 3) diagnosed recurrent rectal carcinoma; 4) history of organ/stem cell transplantation; 5) HIV infection; 6) untreated active hepatitis B or C; 7) receipt of any vaccination within 30 days before treatment initiation; 8) pregnant/lactating; and 9) severe uncontrolled systemic disease. Eligible patients were assigned to 1 of 2 groups based on the treatment they received. This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (No. 2025-KY-1232).
FIGURE 1.
The CONSORT diagram of this study. cCR = clinical complete response; CONSORT = Consolidated Standards of Reporting Trials; LCRT = long-course chemoradiotherapy plus chemotherapy; pCR = pathological complete response; PD = progression disease; SCRT = short-course radiotherapy plus immunotherapy; TNT = total neoadjuvant therapy.
Radiotherapy and Chemotherapy for TNT
The radiotherapy method used was volumetric modulated arc therapy (VMAT) for all but 1 patient who received using intensity modulated radiation therapy (IMRT). The gross tumor volume included the primary tumor and involved lymph nodes, which were indicated by endoscopy and imaging. The clinical target volume included the gross tumor volume and areas at risk from the primary tumor and lymph nodes. Planning target volume (PTV) was a margin of an extra 0.5 cm from the clinical target volume. In the SCRT group, patients received a total dose of 25 Gy in 5 fractions of 5 Gy per day, without concurrent chemotherapy. In the LCRT group, patients received a total dose of 50.4 Gy/50 Gy/45 Gy with 2 Gy/1.8 Gy per day, delivered in 25 to 28 fractions. In the LCRT group, concurrent chemotherapy consisted of capecitabine 1000 mg/m2, postoperative, twice per day. The prescribed dose and fractionation schedule were in accordance with the National Comprehensive Cancer Network (NCCN) guidelines.
The consolidation or induction chemotherapy included CAPOX (oxaliplatin 130 mg/m2 IV on day 1 and capecitabine 1000 mg/m2 twice per day postoperatively for 14 days, repeated every 3 weeks), mFOLFOX6 (oxapliplatin 85 mg/m2 IV glucose tolerance test [IVGTT] on day 1, leucovorin 400 mg/m2 IVGTT on day 1, 5-fluorouracil 400 mg/m2 IVGTT bolus on day 1 followed by 1200 mg/m2/d for 2 days, repeated every 2 weeks), or FOLFIRI (irinotecan 180 mg/m2 IVGTT on day 1, leucovorin 400 mg/m2 IVGTT on day 1, 5-fluorouracil 400 mg/m2 IVGTT bolus on day 1 followed by 1200 mg/m2/d for 2 days, repeated every 2 weeks). The chemotherapy doses were followed according to recommendations from the clinical practice guidelines for rectal cancer of the NCCN.
Surgery
The modes of operation included local excision, total mesorectal excision, abdominoperineal resection, and resection with end colostomy and closure of the distal rectal segment. The approach depended on the status of the disease after the course of TNT, which was evaluated by radiologists and decided by surgeons.
Evaluation and Follow-up
Enhanced pelvic MRI, CT, and colonoscopy with multipoint biopsy were used for evaluation. Laboratory evaluation was performed every time before chemotherapy and weekly during radiotherapy for toxicity evaluation. A clinical complete response (cCR) was defined as the negative findings in the primary tumor and involved lymph nodes by multipoint biopsy and imaging. pCR was determined by postoperative pathology. Partial response (PR) was defined as a reduction of at least 30% in the sum of the longest diameter of the largest cross-section of the primary tumor and the shortest diameter of the largest cross-section of measurable lymph node lesions, relative to baseline. Progressive disease (PD) was defined as an increase of 20% or more in the sum of the longest diameter of the largest cross-section of the primary lesion and the shortest diameter of the largest cross-section of measurable lymph node lesions, relative to baseline, or the appearance of new lesions. Stable disease was defined as neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, falling between these 2 thresholds. Therapeutic response was assessed using the Response Evaluation Criteria In Solid Tumors. The analysis population comprised enrolled patients who met the following criteria: completion of 75% or more of prescribed radiation fractions and receipt of at least 1 cycle of systemic therapy.
Outcomes
The primary end point of this study was pCR. The secondary end points were the rate of sphincter preservation, disease-free survival (DFS), and overall survival (OS). The median DFS was defined as the time point at which 50% of patients experienced disease recurrence, whereas the other 50% remained disease-free. The median OS refers to the time when 50% of patients have died and 50% remain alive. Sphincter preservation after TNT was defined as 1) achieving cCR and declining completion surgery and 2) avoiding abdominoperineal resection. Sphincter preservation at 6 months after TNT was defined as 1) maintaining sustained cCR, 2) undergoing transanal resection or low anterior resection, and 3) for patients who received a temporary stoma, successful closure of the stoma within 6 months. Adverse events (AEs) were summarized. The National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 was applied to AE evaluation during the course of TNT.
Statistics
The χ2 test or the Fisher exact test was used to compare the distributions of the baseline information of patients between the 2 groups. Kaplan-Meier survival curves were used to analyze the survival outcomes. The log-rank test was used to compare the statistical differences between Kaplan-Meier curves. P values were 2-sided, and a p value of <0.05 was considered statistically significant. Statistical analyses were performed using SPSS (version 26) and GraphPad Prism (version 8).
RESULTS
Baseline Characteristics
One hundred twenty-eight patients were enrolled in the SCRT group and 64 patients were enrolled in the LCRT group (Fig. 1). The median age of the patients was 57 years in the SCRT group (interquartile range 47–63) and 56 years in the LCRT group (interquartile range 50–69). The percentage of patients with stage III disease was 84.3% (108/128) and 86% (55/64), respectively. There were 20 patients (15.7%) and 9 patients (14.0%) in the SCRT and LCRT groups, respectively, with stage I or II disease, respectively. Three patients (2.3%) in the SCRT group and 1 (1.6%) in the LCRT group had deficient mismatch repair/microsatellite instability-high disease. These 4 patients were diagnosed in 2021, when ICIs were not yet a standard treatment option. The baseline characteristics were comparable between the 2 groups (Table 1).
TABLE 1.
Baseline information of patients undergoing SCRT or LCRT for locally advanced rectal carcinoma
| Characteristics | SCRT | LCRT | p |
|---|---|---|---|
| (N = 128) | (N = 64) | ||
| Age, median (IQR) | 57 (47–63) | 56 (50–69) | 0.11 |
| Sex, n (%) | 0.24 | ||
| Male | 79 (61.7) | 45 (70.3) | |
| Female | 49 (38.3) | 19 (29.7) | |
| TNM staging at diagnosis, n (%) | |||
| T | 0.14 | ||
| T1 | 0 | 0 | |
| T2 | 28 (21.9) | 12 (18.7) | |
| T3 | 94 (73.4) | 44 (68.8) | |
| T4 | 6 (4.7) | 8 (12.5) | |
| N | 0.10 | ||
| N0 | 20 (15.6) | 9 (14.0) | |
| N1 | 62 (48.5) | 41 (64.1) | |
| N2 | 46 (35.9) | 14 (21.9) | |
| AJCC stage | |||
| Ia | 12 (9.4) | 2 (3.1) | |
| IIA | 8 (6.3) | 7 (10.9) | |
| IIIA | 12 (9.4) | 10 (15.6) | |
| IIIB | 94 (73.4) | 41 (64.1) | |
| IIIC | 2 (1.5) | 4 (6.3) | |
| MRF (+), n (%) | 87 (68.0) | 47 (73.4) | 0.44 |
| EMVI (+), n (%) | 47 (36.7) | 33 (51.6) | 0.08 |
| Distance from the anal verge, cm | 0.001 | ||
| Range | 0–13 | 0–13 | |
| Median | 3.5 | 5.0 | |
| ≥10, n (%) | 1 (0.7) | 4 (6.3) | |
| ≥5, <10, n (%) | 39 (30.5) | 34 (53.1) | |
| <5, n (%) | 88 (68.8) | 26 (40.6) | |
| Size of the lesion, cm | 0.28 | ||
| Range | 1.8–11.3 | 1.7–15 | |
| Median | 5.1 | 5.5 | |
| Pathology, n (%) | 0.72 | ||
| Adenocarcinoma | 125 (97.7%) | 63 (98.4%) | |
| Signet-ring cell carcinoma | 3 (2.3%) | 1 (1.6%) | |
| MMR/MSI status, n (%) | 0.37 | ||
| pMMR/MSS | 95 (74.3%) | 42 (65.6%) | |
| dMMR/MSI-H | 3 (2.3%) | 1 (1.6%) | |
| Unknown | 30 (23.4%) | 21 (32.8%) | |
| ECOG score, n (%) | 1.00 | ||
| 0–1 | 125 (97.7%) | 63 (98.4%) | |
| 2 | 3 (2.3%) | 1 (1.6%) |
AJCC = American Joint Committee on Cancer; dMMR = deficient mismatch repair; ECOG = Eastern Cooperative Oncology Group; EMVI = extramural venous invasion; IQR = interquartile range; MRF = mesorectal fascia; MSI = microsatellite instability; MSI-H = microsatellite instability-high; MSS = microsatellite stable; pMMR = proficient MMR.
aPatients with stage I disease were included if cancer was <5 cm from the anal version (Stage I T1, T2 N0 M0, as AJCC TNM Staging System for Rectal Cancer 8th ed, 2017 recommended by NCCN).
TNT Compliance
Of the 128 patients in the SCRT group, the course of radiotherapy was interrupted in 19 patients, but all of them completed radiotherapy. Thirteen patients were interrupted because of pain/radiation enteritis (manifested as diarrhea), 3 owing to hemorrhage (grade 1–2, treatment paused for safety), and 3 for personal reasons. During the course of TNT in this group, the treatment of 1 patient aged 69 years was terminated because of pneumonia, which ultimately resulted in respiratory failure. In the LCRT group, the course of radiotherapy was interrupted and completed in 2 patients. The course was interrupted but incomplete in 4 patients, who missed 1, 2, 3, and 6 fractions, respectively. The treatment of 2 patients was terminated because of heart failure (80 years) and cerebral infarction (69 years), respectively. Two patients discontinued treatment: 1 because of grade 3 radiation enteritis, and the other because of grade 4 granulocytopenia. The proportion of radiotherapy interruption was significantly higher in the SCRT group than in the LCRT group (14.8% vs 3.1%, p = 0.014); conversely, the rate of incomplete radiotherapy was lower in the SCRT group (0% vs 6.4%, p = 0.012). In the SCRT group, 77.3% of patients (99/128) received 4 to 6 cycles of chemotherapy, compared to 64.1% (41/64) in the LCRT group. Treatment deviations were observed: 15.6% (20/128) of SCRT patients discontinued chemotherapy early for surgery, whereas 7.0% (9/128) exceeded 6 cycles owing to surgical delays. In the LCRT group, 18.7% (12/64) completed fewer than 4 cycles, and 17.2% (11/64) completed more than 6 cycles. Despite these variations, all patients met the analytical inclusion criteria.
Detailed information on TNT is summarized in Table 2. The median duration of TNT was 3.9 weeks (ranging from 0.6 to 9.9 weeks) for the SCRT group and 5.4 weeks (ranging from 2.4 to 19.1 weeks) for the LCRT group.
TABLE 2.
Information about TNT for patients with locally advanced rectal carcinoma
| Characteristics |
SCRT (N = 128) |
LCRT (N = 64) |
|---|---|---|
| Mode of TNT, n (%) | ||
| Radiation + consolidation-chemotherapy | 111 (86.7) | 30 (46.9) |
| Induction-chemo + radiation+consolidation-chemotherapy | 17 (13.3) | 34 (53.1) |
| Chemotherapy for induction, n (%) | ||
| Oxaliplatin-based (CAPOX or FOLFOX) | 9 (7.0) | 30 (46.9) |
| Oxaliplatin-based (CAPOX or FOLFOX)+PD-1 inhibitor | 6 (4.7) | 0 |
| Irinotecan-based (FOLFIRI) | 0 | 4 (6.3) |
| PD-1 inhibitor alone | 2 (1.6) | 0 |
| Radiation | ||
| Dose received, cGy | 2500 cGy | 4500/5000/5040 cGy |
| Tumor boost, n (%) | 0 | 21 (32.8) |
| Modality | ||
| VMAT | 128 (100.0) | 63 (98.4) |
| IMRT | 0 | 1 (1.6) |
| Interrupted and completed | 19 (14.8) | 2 (3.1) |
| Interrupted but incomplete | 0 | 4 (6.3) |
| Concurrent chemotherapy, n (%) | ||
| Capecitabine | 0 | 45 (70.3) |
| CAPOX or FOLFOX | 2 (1.6) | 8 (12.5) |
| Not received | 126 (98.4) | 11 (17.2) |
| Chemotherapy for consolidation, n (%) | ||
| Oxaliplatin-based (CAPOX or FOLFOX) | 0 | 50 (78.2) |
| Oxaliplatin-based (CAPOX or FOLFOX) + PD-1 inhibitor | 123 (96.1) | 0 |
| Irinotecan-based (FOLFIRI) | 0 | 5 (7.8) |
| Irinotecan-based (FOLFIRI) + PD-1 inhibitor | 1 (0.8) | 0 |
| PD-1 inhibitor alone | 2 (1.6) | 2 (3.1) |
| Not received | 2 (1.6) | 7 (10.9) |
| Duration of TNT, wk | ||
| Range | 0.6–9.9 | 2.4–19.1 |
| Median | 3.9 | 5.4 |
CAPOX = capecitabine and oxaliplatin; sFOLFOX = folinic acid, fluorouracil, and oxaliplatin; FOLFIRI = irinotecan, leucovorin, 5-fluororuracil; IMRT = intensity-modulated radiotherapy; PD-L1, programmed death-ligand 1; LCRT = long-course chemoradiotherapy plus chemoradiotherapy; PD-1 = programmed cell death protein 1; SCRT = short-course radiotherapy plus immunotherapy; TNT = total neoadjuvant therapy; VMAT = volumetric modulated arc therapy.
Efficacy
The rates of pCR for the SCRT group and the LCRT group were 42.2% (54/128) and 15.6% (10/64), respectively. The difference was statistically significant with a p value of 0.001. Few patients in either group proceeded to “watch and wait” following cCR owing to the limited acceptance of this strategy at the time. In the SCRT group, the rate of pCR for patients who received the operation within 5 weeks was 44.8%, whereas the rate of pCR for patients who received the operation after 5 weeks was 78.6%. The rate of the latter was significantly higher than that of the former (p = 0.02). In the SCRT group, 4 patients (3.1%) had disease progression during the course of TNT, and 2 patients (1.6%) refused surgery for personal reasons. One hundred ten patients (85.9%) received the operation in the SCRT group, and R0 resection was achieved in 108 patients (98.2%). By contrast, 2 patients (3.1%) experienced disease progression in the LCRT group, and 8 patients (12.5%) refused surgery, leaving 47 patients (73.4%) who received surgery. The proportion of patients who refused surgery was significantly higher in the LCRT group than in the SCRT group (p = 0.003), which contributed to the higher overall operative rate observed in the SCRT group (Table 3). Forty-six patients (97.9%) achieved R0 resection. Postoperative pathology results are summarized in Table 3. The rate of sphincter preservation in the SCRT group was 75.8%, which was higher than that in the LCRT group (65.6%), but it was not statistically significant (p = 0.138). Information regarding adjuvant therapy is summarized in Supplemental Table 1 (https://links.lww.com/DCR/C623).
TABLE 3.
Outcomes of TNT for patients with locally advanced rectal carcinoma
| Category | SCRT (N = 128) | LCRT (N = 64) | p |
|---|---|---|---|
| cCR after TNT, n (%) | 77 (60.2) | 27 (42.2) | 0.018 |
| Received cCR and watch & wait, n (%) | 11 (8.6) | 5 (7.8) | 0.85 |
| PR after TNT, n (%) | 14 (10.9) | 19 (29.6) | 0.001 |
| SD after TNT, n (%) | 42 (32.8) | 24 (37.5) | 0.519 |
| PD during TNT (without surgery), n (%) | 4 (3.1) | 2 (3.1) | 1.00 |
| PD after TNT (received salvage surgery), n (%) | 2 (1.6) | 2 (3.1) | 0.602 |
| Inoperable due to complications, n (%) | 1 (0.7) | 2 (3.1) | 0.26 |
| Refused operation, n (%) | 2 (1.6) | 8 (12.5) | 0.003 |
| Received operation, n (%) | 110 (85.9) | 47 (73.4) | 0.03 |
| Interval from the end of radiotherapy to surgery, wk | |||
| Range | 0.4–9.7 | 1.1–16.0 | |
| Median | 3.5 | 2.5 | |
| Surgical procedure | |||
| Transanal resection of rectal tumor | 15 (11.7) | 4 (6.3) | 0.309 |
| Low anterior resection | 75 (58.6) | 31 (48.4) | 0.182 |
| Abdominal perineal resection | 20 (15.6) | 12 (18.7) | 0.584 |
| Postoperative pathology status, n (%) | |||
| ypT classification, n (%) | |||
| T0 | 54 (42.2) | 11 (17.2) | 0.001 |
| Tis | 1 (0.7) | 1 (1.6) | 1.000 |
| T1 | 4 (3.1) | 1 (1.6) | 0.666 |
| T2 | 17 (13.3) | 14 (21.8) | 0.127 |
| T3 | 33 (25.8) | 17 (26.6) | 0.907 |
| T4 | 1 (0.7) | 3 (4.6) | 0.109 |
| ypN classification, n (%) | |||
| N-negative | 90 (70.3) | 31 (48.4) | 0.003 |
| N-positive | 20 (15.6) | 16 (25.0) | 0.117 |
| Resection status | 1.00 | ||
| R0 | 108 (84.4) | 46 (71.9) | |
| R1 | 2 (1.6) | 1 (1.6) | |
| R2 | 0 | 0 | |
| pCR | 54 (42.2) | 10 (15.6) | 0.001 |
| Non-pCR | 56 (43.8) | 37 (57.8) | |
| Sphincter preservation, n (%) | |||
| After TNT/surgery | 97 (75.8) | 42 (65.6) | 0.138 |
| 6 mo after TNT/surgery | 93 (72.7) | 41 (64.1) | 0.222 |
The definition of the therapeutic evaluation was described in the Methods section under Evaluation and Follow-up.
cCR = clinical complete response; LCRT = long-course chemoradiotherapy plus chemoradiotherapy; pCR = pathological complete response; PD = progressive disease; PR = partial response; SCRT = short-course radiotherapy plus immunotherapy; SD = stable disease; TNT = total neoadjuvant therapy.
Survival
With a median follow-up of 42.3 months (95% CI, 40.538–43.990), a total of 121 patients in the SCRT group and 51 patients in the LCRT group were evaluated for DFS. The median DFS was not reached in the SCRT group but was 28.3 months in the LCRT group (p = 0.03; HR 0.46; 95% CI, 0.205–1.040; Fig. 2). The median OS was not reached for either group (p = 0.02; HR 0.33; 95% CI, 0.118–0.910; Fig. 3). At final follow-up, in the SCRT group, 17 patients developed relapse and 7 patients died; in the LCRT group, 11 patients relapsed and 10 patients died. All patients who achieved cCR and followed “watch and wait” remained disease-free. Among those who refused surgery, disease progression occurred in 2 SCRT and 4 LCRT patients. Detailed information is summarized in Supplemental Table 2 (https://links.lww.com/DCR/C623). The percentage of 6-month sphincter preservation was 72.7% in the SCRT group versus 64.1% in the LCRT group (p = 0.222).
FIGURE 2.
Kaplan-Meier curve analyses of DFS between the SCRT group and the LCRT group. DFS = disease-free survival; LCRT = long-course chemotherapy plus chemoradiotherapy; SCRT = short-course radiotherapy plus immunotherapy.
FIGURE 3.
Kaplan-Meier curve analyses of OS between the SCRT group and the LCRT group. LCRT = long-course chemoradiotherapy plus chemoradiotherapy; OS = overall survival; SCRT = short-course radiotherapy plus immunotherapy.
Safety
The detailed treatment-related AEs are listed in Table 4. During the course of TNT, 41 of 128 patients (32.0%) experienced grade 3 or 4 treatment-related AEs in the SCRT group. In comparison, 14 of 68 patients (21.9%) experienced grade 3 and 4 treatment-related AEs in the LCRT group. The difference between the 2 groups was not statistically significant (p = 0.14). The most common grade 3 and 4 treatment-related AEs were hematological toxicity for both groups. The incidence of grade 3 and 4 radiation enteritis was higher in the SCRT groups than in the LCRT group (7.0% vs 0%, p = 0.03). The incidence of grade 1 and 2 anal pain or defecating pain was relatively higher in the SCRT group (48.4% vs 25.5%, p = 0.002).
TABLE 4.
Adverse events
| Adverse events and grade |
SCRT,
n (%) |
LCRT,
n (%) |
p |
|---|---|---|---|
| Grade 0 | 0 | 0 | |
| Grade 1–2 | 87 (68.0) | 50 (78.1) | 0.14 |
| Grade 3–4 | 41 (32.0) | 14 (21.9) | 0.14 |
| Hematological toxicity | |||
| Grade 0 | 5 (3.9%) | 5 (7.8%) | 0.25 |
| Grade 1–2 | 90 (70.3%) | 47 (73.4%) | 0.65 |
| Grade 3–4 | 33 (25.8%) | 12 (18.8%) | 0.28 |
| Radiation enteritis | |||
| Grade 0 | 22 (17.2%) | 19 (29.7%) | 0.046 |
| Grade 1–2 | 97 (75.8%) | 45/ 70.3% | 0.42 |
| Grade 3–4 | 9 (7.0%) | 0 | 0.03 |
| GI toxicity | |||
| Grade 0 | 35 (27.3%) | 35 (54.7%) | 0.0001 |
| Grade 1–2 | 93 (72.7%) | 29 (45.3%) | 0.0001 |
| Grade 3–4 | 0 | 0 | |
| Hypokalemia | |||
| Grade 0 | 82 (64.1%) | 44 (68.8%) | 0.52 |
| Grade 1–2 | 43 (33.6%) | 19 (29.7%) | 0.59 |
| Grade 3–4 | 3 (2.3%) | 1 (1.6%) | 1.00 |
| Hyponatremia | |||
| Grade 0 | 105 (82.0%) | 60 (93.8%) | 0.03 |
| Grade 1–2 | 23 (18.0%) | 4 (6.2%) | 0.03 |
| Grade 3–4 | 0 | 0 | |
| Radiodermatitis | |||
| Grade 0 | 107 (83.6%) | 52 (81.3%) | 0.80 |
| Grade 1–2 | 20 (15.6%) | 12 (18.8%) | 0.58 |
| Grade 3–4 | 1 (0.8%) | 0 | >0.99 |
| Pain | |||
| Grade 0 | 64 (50.0%) | 48 (75.0%) | 0.001 |
| Grade 1–2 | 62 (48.4%) | 16 (25.5%) | 0.002 |
| Grade 3–4 | 2 (1.6%) | 0 | 0.55 |
| Hemorrhage | |||
| Grade 0 | 88 (68.8%) | 52 (81.2%) | 0.07 |
| Grade 1–2 | 39 (30.5%) | 12 (18.8%) | 0.08 |
| Grade 3–4 | 1 (0.8%) | 0 | >0.99 |
| Stenosis | 9 (7.0%) | 0 | 0.03 |
| Fistula | 8 (6.3%) | 0 | 0.05 |
| Hernia | 2 (1.6%) | 1 (1.6%) | >0.99 |
| Hypothyroidism | 2 (1.6%) | – | |
| Hypopituitarism | 1 (0.8%) | – |
LCRT = long-course chemoradiotherapy plus chemoradiotherapy; SCRT = short-course radiotherapy plus immunotherapy.
Nine patients developed postoperative rectal stenosis requiring dilation in the SCRT group. There were 8 patients who had a postoperative rectal fistula. No patients had stenosis or fistula in the LCRT group. The difference in stenosis was statistically significant (p = 0.03), whereas no significant difference was observed for rectal fistula (p = 0.05). Two patients had hypothyroidism, and 1 patient had hypopituitarism in the SCRT group, which were considered as the immune-related AEs.
DISCUSSION
In this retrospective study, we investigated the efficacy of short-course radiation integrated with immunochemotherapy versus long-course chemoradiation integrated with chemotherapy as the modality of TNT for the patients diagnosed with rectal carcinoma, with the majority of the enrolled patients having locally advanced disease (84.3% in the SCRT group, 86% in the LCRT group). The main results demonstrated that, as the modality of TNT, short-course radiation integrated with immunochemotherapy exhibited a higher pCR rate than LCRT plus chemotherapy. Our data indicated that, in the SCRT group, patients who underwent surgery after 5 weeks had a higher pCR rate than those who underwent surgery within 5 weeks (78.6% vs 44.8%, p = 0.02). The rate of R0 resection and sphincter preservation was similar in both groups. With a median follow-up of 42.3 months (95% CI, 40.538–43.990), the median DFS of the SCRT group was not reached while it was reached at 28.3 months in the LCRT group (p = 0.03; HR 0.46; 95% CI, 0.205–1.040). The median OS for both groups was not reached (p = 0.02; HR 0.33; 95% CI, 0.118–0.910).
Several prospective clinical trials that explored the efficacy of short-course radiation combined with immunotherapy have reported their latest results. The clinical trial of TORCH randomly assigned subjects into 2 groups: 1) short-course radiation followed by consolidation immunochemotherapy (n = 62) and 2) induction immunochemotherapy followed by short-course radiation and consolidation immunochemotherapy (n = 59). The rate of CR for the 2 groups was 56.5% and 54.2%, respectively.17 Compared with these data, the rate of pCR in our study was lower. It was considered that the decrease may be caused by fewer cycles of chemotherapy (77.3%) and the increased sample size (n = 128). The rate of pCR from the UNION trial was similar to our data, which was 39.8% in the short-course radiation followed by 2 cycles of immunochemotherapy group and 15.3% in the long-course chemoradiation followed by 2 cycles of chemotherapy group.18 This finding indicates a potential that 2 cycles of consolidation therapy were not an optimal choice for TNT, regardless of either mode of radio-integration. The final pCR rate reported by the study of Averectal was 37.5%,20 whereas the ICI used in the study was avelumab. In a retrospective study that focused on the short-course radiation modality, the rate of pCR was 55.6% in the short-course radiation followed by consolidation immunotherapy group and 53.6% in the induction immunotherapy followed by short-course radiation and consolidation immunotherapy group.21 The pCR rate of the SCRT group in our study was, by and large, consistent in a horizontal comparison. Several phase II or III trials are ongoing, including STELLAR and APRAM, with results yet to be uncovered. The lower pCR rate observed in our LCRT group is likely explained by 2 protocol differences. First, the radiation doses delivered in our cohort (4500 cGy for 14.1%, 5000 cGy for 79.7%, and 5040 cGy for 6.2%) were lower than the median dose of 5400 cGy used in reference trials (eg, OPRA).22 In accordance with NCCN guidelines, we did not prescribe doses exceeding 5400 cGy, as this dose is the recommended threshold for unresectable disease. This approach contrasts with trials such as OPRA, which used a broader dose range of 5040 to 5600 cGy. Second, although 64.1% of our patients completed the planned 4 to 6 chemotherapy cycles, a substantial proportion received fewer (fewer than 4 cycles: 18.7%) or more (more than 6 cycles: 17.2%) cycles, differing from the fixed 8 cycles in the OPRA trial.22 These key differences in treatment exposure likely contributed to the observed pCR rate in our real-world cohort.
It is worth noting that we bring a cutoff time for the interval from the end of SCRT to the time of surgery. So far, there is no clearly recommended interval for the optimal duration from the end of SCRT to the time of surgery. In 2010, Pettersson et al23 reported the results of a phase III trial that compared the rate of CR among 3 groups: 1) short-course radiotherapy and immediate operation, 2) short-course radiotherapy and delayed operation, and 3) long-course chemoradiotherapy and delayed operation.23 Results showed that the rate of CR for the second group was statistically higher than that in the first group and similar to that in the third group. These data provided evidence for the delayed operation after short-course radiotherapy. No further studies focused specifically on the duration from the end of short-course radiotherapy to the time of surgery. In this study, a higher rate of pCR was achieved in the patients who underwent the operation 5 weeks after the end of SCRT in the mode of SCRT integrated with immunochemotherapy. Although it needs further studies to verify, it provides a potential time point for clinical management.
The duration of TNT in both groups was relatively shorter than reported in other studies, largely due to variations in the number of chemotherapy cycles administered. As noted in the treatment compliance section, 77.3% of patients in the SCRT group completed 4 to 6 cycles of chemotherapy. The median duration was reduced mainly because 20 patients (15.6%) declined further chemotherapy after 1 to 2 cycles and proceeded directly to surgery. In the LCRT group, 64.1% of patients received the planned 4 to 6 cycles. The treatment duration was shortened for 12 patients who received fewer than 4 cycles, including 1 patient with heart failure, 1 with cerebral infarction, and 10 who declined further treatment after achieving PR or stable disease. Importantly, as all enrolled patients met the predefined criteria for inclusion in the analysis, potential bias was minimized, and the reliability of the findings was strengthened.
Nevertheless, the median DFS and median OS were immature; our study provided a trend in potential DFS and OS with a median follow-up of 42.3 months. We presented the potential superiority of DFS and OS in the SCRT group with the HR. In our data, the efficacy of SCRT integrated with immunotherapy was overmatched compared with that of long-course chemoradiation integrated with chemotherapy, for both short- and long-term outcomes. In addition, the majority of patients in our study were proficient MMR/microsatellite stable (74.3% of the SCRT groups and 65.6% of the LCRT group). With incomplete information on the level of programmed death-ligand 1 expression, the efficacy of the SCRT group outperformed that of the LCRT group, which indicates the superiority may be independent of the expression level of programmed death-ligand 1.
From the aspect of safety, it seems the short-course radiation with immunotherapy group had a relatively higher incidence of radiation enteritis, GI toxicity, electrolyte disturbance of hyponatremia, and pain in the anus compared with the LCRT group. All the mentioned treatment-related AEs were alleviated with symptomatic treatment and were considered controllable. The incidence of postoperative stenosis was significantly higher in the SCRT group, and the incidence of rectal fistula also showed an upward trend that approached statistical significance (p = 0.054). The literature review shows no clear evidence that short-course radiation plus ICIs elevates these risks.17,18,20,22,24 The elevated risk in some studies is postulated to stem from late radiation effects.25,26 Conversely, others report no difference between short- and long-course radiotherapy.27,28 Although our study provides data from real-world practice, its retrospective nature restricts definitive conclusions. Prospective, multicenter, randomized trials are necessary to determine whether short-course radiotherapy combined with immunochemotherapy elevates the risk of stenosis or rectal fistula. The course of radiotherapy was interrupted in 19 patients (14.8%) in the SCRT group, whereas the number of interruptions was 6 (9.4%), with 4 (6.3%) of them incomplete chemoradiotherapy, in the LCRT group. Concurrent treatment regimen and symptomatic supportive care is expected to be modified in the modality of short-course radiation integrated with immunotherapy to relieve treatment-related symptoms, which may help improve compliance. The combination of programmed cell death protein 1 inhibitors did not elevate the treatment-related AEs.
Indubitably, this study had limitations as a retrospective study. Although the data were retrieved within the hospital, symptomatic treatments were administered by different radiologists and surgeons, which may underestimate or overestimate the grades of treatment-related AEs to some degree. Another limitation was the ratio between the 2 groups. Considering the number of patients in the SCRT group was twice that in the LCRT group, this raises a valid concern about overestimation in the LCRT group. From a statistical aspect, it may give more confidence to the preponderance of the SCRT group.
This retrospective study was to preliminarily investigate the efficacy of the 2 TNT modalities. Further studies have been designed to prospectively determine the efficacy of short-course radiation integrated with immunochemotherapy and long-course chemoradiation with immunochemotherapy, making the mode of radiotherapy the variable, and to explore potential indicators for stratification and clinical decision-making.
CONCLUSIONS
The integration of short-course radiation plus immunotherapy exhibits a higher rate of pCR than LCRT in the modality of TNT for locally advanced rectal carcinoma, and the former presents a trend of dominance for long-term survival. Further prospective studies will focus on the comparison between short-course radiation versus long-course chemoradiation with immunotherapy.
ACKNOWLEDGMENTS
The authors thank all patients for consenting to share their data for this study. We also sincerely thank the editors for their valuable suggestions.
Supplementary Material
Footnotes
Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML and PDF versions of this article on the journal’s website (www.dcrjournal.com).
Funding/Support: This study was supported by the Technology Research Project of the Education Department in Henan Province (No. 24A320055) and the Natural Science Foundation of Henan Province (No. 242300421491).
Financial Disclosure: None reported.
Contributor Information
Chang Su, Email: suchang0720@zzu.edu.cn.
Yugui Lian, Email: fcclianyg@zzu.edu.cn.
Xiangbo Wan, Email: wanxbo@zzu.edu.cn.
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