Neoplasms

Digestive System Diseases

All Conditions

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Oxaliplatin

Capecitabine

Antimetabolites

Patients diagnosed with locally advanced very low rectal cancer were chosen to undergo a total neoadjuvant therapy (TNT) regimen. This regimen consisted of preoperative fractionated radiotherapy (5×7Gy) combined with 6 cycles of CAPOX chemotherapy and enverolimab.

For patients who achieved clinical complete response (cCR) or near-clinical complete response (ncCR) after TNT, an organ-preserving strategy involving local full-thickness resection was implemented. Patients who achieve non-clinical complete response are subjected to traditional TME surgery.

After reaching a cumulative radiotherapy dose of 25Gy in the entire pelvic cavity (PTV1), the treatment field was subsequently narrowed to solely focus on the primary tumor (PTV2), with a total dose of 35Gy administered. All patients will undergo fractionated radiotherapy, following a regimen of 7Gy per fraction, delivered every 3 weeks for five cycles.

split-course hypofraction radiotherapy

Drug: Oxaliplatin,130mg/m2，ivgtt，d1,for 6 cycles. Drug: Capecitabine,1000mg/m2，po，bid，d1-14, for 6 cycles.

CAPOX

Envafolimab is administered by subcutaneous injection. The recommended dose is 300 mg per 3 weeks (Q3W) for 6 cycles.

Envafolimab

Local full-thickness resection is employed for patients with clinical complete response (cCR) or near-clinical complete response (ncCR) following TNT.

Local excision

Pan Chi, MD

Jiabin Zheng

Patients diagnosed with locally advanced very low rectal cancer were chosen to participate in a comprehensive neoadjuvant therapy (TNT) protocol. This treatment regimen consisted of preoperative fractionated radiotherapy (5×7Gy) combined with 6 cycles of CAPOX chemotherapy and enverolimab. For patients who achieved clinical complete response (cCR) or near-clinical complete response (ncCR) after undergoing TNT, an organ-preserving strategy involving local full-thickness resection was implemented.

Locally advanced very low rectal cancer poses significant challenges in rectal cancer treatment. Presently, the prevailing approach in clinical practice involves neoadjuvant chemoradiotherapy in conjunction with total mesorectal excision (TME). Historically, abdominoperineal resection (APR) has been the conventional surgical procedure for managing locally advanced very low rectal cancer. However, the long-term presence of a colostomy following an abdominoperineal resection (APR) significantly impacts the quality of life for patients. Additionally, studies have revealed that 11.8-22% of rectal cancer patients who underwent APR after neoadjuvant chemoradiotherapy (nCRT) achieved a pathological complete response (pCR). Conversely, 11-52% of patients with pCR after nCRT for rectal cancer ultimately underwent APR surgery. Intersphincter resection (ISR) offers a highly beneficial surgical approach that preserves the anal sphincter, particularly for individuals with locally advanced very low rectal cancer. The patient's postoperative quality of life was significantly affected by severe low anterior resection syndrome (LARS), sexual dysfunction, and voiding dysfunction.

This study represents an exploratory phase II clinical trial in which patients diagnosed with locally advanced very low rectal cancer were chosen to undergo a total neoadjuvant therapy (TNT) regimen. This regimen consisted of preoperative fractionated radiotherapy (5×7Gy) combined with 6 cycles of CAPOX chemotherapy and enverolimab.

For patients who achieved clinical complete response (cCR) or near-clinical complete response (ncCR) after undergoing TNT, an organ-preserving strategy involving local full-thickness resection was implemented. Patients who achieve non-clinical complete response are subjected to traditional TME surgery.

This study aims to investigate the effectiveness and safety of organ preservation using the local resection approach in patients with locally advanced very low rectal cancer. By implementing this approach, the study aims to improve the quality of life for patients who achieve pathological complete response (pCR), thereby avoiding the need for conventional abdominoperineal resection (APR) and intersphincteric resection (ISR) procedures. Additionally, this study aims to address the issue of local regrowth associated with the "watch \& wait" strategy and propose a novel treatment strategy for rectal-sparing surgery in patients with locally advanced very low rectal cancer.

Organ Preservation Following Enverolimab-based Total Neoadjuvant Therapy for Locally Advanced Very Low Rectal Cancer

Total Neoadjuvant Therapy With Split-course Hypofraction Radiotherapy Combined With CAPOX and Envafolimab Followed by Local Excision for Locally Advanced Very Low Rectal Cancer: an Open-label, Single-arm, Multi-center, Phase II Trial

The rectum is intact, owing to no radical total mesorectal excision (TME), curative (R0) salvage surgery by local excision (LE), and no permanent stoma (including a never reversed protective stoma or a stoma owing to toxicities and/or poor functional outcomes).

The proportion of subjects with primary rectal cancer assessed by hematoxylin and eosin staining including no evidence of primary tumor (T0) or carcinoma in situ: intramucosal carcinoma (invading lamina propria, not infiltrating muscularis mucosa) (Tis) or tumor invading submucosa (T1) (ypT0-1 based on the latest UICC/AJCC staging system)

Proportion of subjects with primary rectal cancer and all sampled lymph nodes who did not find any invasive carcinoma and high-grade intraepithelial neoplasia/severe dysplasia after assessment by hematoxylin and eosin staining (Judged as ypT0N0 stage according to the latest UICC/AJCC staging system)

Acute and late toxicity, Incidence of Treatment-Emergent Adverse Events assessment according to NCICTCAE V.5.0

The proportion of patients in all subjects within 3 years from the start of the surgery to detection of a tumor involving the bowel wall only that occurs after LE or TME

The proportion of patients in all subjects within 3 years from the start of the surgery to detection of a tumor involving either the bowel wall, mesorectum, and/or pelvic organs that occurs after LE or TME

The proportion of patients in all subjects within 3 years from the start of the surgery to recurrence, distant metastsis, or death from any cause (whichever occurs first)

Quality of life measured using EORTC QLQ-C30 and EORTC QLQ-CR29

池畔

Professor

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Immune Checkpoint Inhibitors

Immunomodulating Agents

Irradiation of 60-68Gy/15-17f is administered followed by one-year immunotherapy maintenance.

Irradiation of 48Gy/12f is administered followed by one-year immunotherapy maintenance.

Patients in this arm would receive high-dose fractionated radiotherapy with 60-68Gy/15-17f with one-year immunotherapy maintenance.

High-dose fractionated radiotherapy

Patients in this arm would receive high-dose fractionated radiotherapy with 48Gy/15-12f with one-year immunotherapy maintenance.

Low-dose fractionated radiotherapy

Xiaoyang Li, M.D.

Dong Qian, M.D.

Definitive concurrent chemoradiotherapy followed by durvalumab (Pacific protocol) has been the standard modality for stage III locally advanced non-small cell lung cancer. In spite of the median overall survival of 47.5 months, there still existed 38.5% and 6.9% patients who finally developed intra-thorax and extra-thorax recurrence respectively in long-term follow-up. The relatively low local control rate has been the bottleneck for further improvement of overall survival. Hypofraction radiotherapy has been validated to be able to increase the local control rate in two prospective trials. Therefore, this trial is designed to explore the safety and primary efficacy of hypofraction radiotherapy followed by immune checkpoint inhibitors for stage III locally advanced non-small cell lung cancer.

Trial title: Hypofraction radiotherapy followed by immune checkpoint inhibitors for locally advanced non-small cell lung cancer: A phase I/II clinical trial.

Trial objective: To explore the safety and primary efficacy of hypofraction radiotherapy followed by immune checkpoint inhibitors for stage III locally advanced non-small cell lung cancer.

Trial Design: To enroll 36 patients diagnosed with stage III locally advanced non-small cell lung cancer to receive hypofraction radiotherapy (18 patients receiving high dose of 60-68 (Gray, Gy) /15-17 (fraction, f) and 18 patients receiving low dose of 48Gy/12f) followed by 1-year maintenance of immune checkpoint inhibitors.

Inclusion Criteria: a. 18-70 years old; b. Eastern Cooperative Oncology Group (ECOG) 0-1; c. non-small cell lung cancer including squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, large-cell carcinoma; d. wild-type of driven genes; e. stage III (AJCC 8th Edition) confirmed by cranial MRI, chest CT, abdominal ultrasonograph, bone scan or cranial MRI and Positron Emission Tomography (PET-CT); f. surgically unresectable or deny of surgery; g. signature of inform consent.

Exclusion Criteria: a. younger than 18 years old or older than 70 years old; b. ECOG\>1; c. small-cell lung cancer and other neuroendocrine carcinoma including typical or atypical carcinoid, large-cell neuroendocrine carcinoma; d. mutant type of driven genes; e. non stage III (AJCC 8th Edition) confirmed by cranial MRI, chest CT, abdominal ultrasonograph, bone scan or cranial MRI and PET-CT; f. surgically resectable; g. no signature of inform consent.

Staging Examination before Radiotherapy: a. ECOG scoring. b. Cranial contrast MRI and PET-CT, or cranial contrast MRI (preferred), chest contrast CT, abdominal ultrasonography and bone scan. c. Bronchoscopy for centrally-located lung cancer. d. Staging examination is mandatory after inductive chemotherapy \& chemotherapy with immunotherapy. e. Pulmonary function test.

Inductive therapy before radiotherapy: Chemotherapy or chemotherapy combined with immunotherapy is allowed as inductive therapy. Detailed regimen could refer to NCCN guidelines. Tyrosine kinase inhibitors are not allowed as inductive therapy.

Randomization: Patients would be randomly assigned to high dose group and low dose group using random number table method.

Radiotherapy CT simulation: 4-Dimensional CT (4D-CT) with intravenous contrast is recommended for simulation. Scan thickness should be less than 5 mm. Thermal mask or vacuum bag is recommended.

Target Delineation: Considering hypofraction and involved field irradiation (IFI), only Internal Tumor Volume (ITV) should be delineated without the need to delineate Clinical Tumor Volume (CTV).

Delineation of ITV: ITV should include pulmonary gross tumor and metastatic mediastinal lymph nodes. PET-CT registration with simulation CT is recommended for patients with obstructive atelectasis. For patients with suspected mediastinal lymph nodes, Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA) is recommended.

Production of Planning Tumor Volume (PTV):

Low Dose Hypofraction Arm (48Gy/12f) PTV: PTV is produced by a margin of 5 mm added to ITV. Modification of PTV is suggested to respect anatomic boundary.

High Dose Hypofraction Arm (60-68Gy/15-17f) PTV: Planning Tumor Volume (PTV) is produced by a margin of 5 mm added to ITV. Modification of PTV is suggested to respect anatomic boundary. For patients with ITV abutting esophagus, the technique of Esophagus-Sparing Simultaneous Integrated Boost (ES-SIB) should be utilized. PTV should be modified not to cover esophagus to ensure that the maximum dose to esophagus should be ≤ 45Gy. The dose to PTV in adjacent to esophagus could be compromised (D99% of PTV should be ≥ 51Gy).

Dosimetric Limitation: 95% prescription dose should cover 100% PTV and 95% PTV should receive 100% prescription dose. Total Lung: V20\<25%, Dmean\<13Gy, V5\<50%. Spinal Cord: Dmax\<40Gy. Heart: V30\<40%, Dmean\<25Gy.

Treatment Implementation: Radiotherapy is implemented every day. Cone-beam CT should utilized every day to minimize set-up error.

Concurrent Chemotherapy: If patients have received over 4 cycles of inductive chemotherapy with or without immunotherapy, no concurrent chemotherapy is needed. If patients have received less than 4 cycles of inductive chemotherapy with or without immunotherapy, concurrent chemotherapy is needed to ensure 4 cycles of chemotherapy. Adenocarcinoma: Pemetrexed combined with platinum is recommended. Squamous-cell lung cancer: Etoposide combined with platinum is recommended. One month after completion of radiotherapy, chest CT and abdominal ultrasonography should be undertaken. After exclusion of disease progression and grade 2 or more radiation-induced pneumonitis, consolidative immunotherapy should be started. Durvalumab maintenance for one year is recommended.

Follow-up: Patients should be follow-up every three months right after the completion of radiotherapy to 3 years after radiotherapy. Then follow-up every half year is allowed to 5 years after radiotherapy. After 5 years, follow-up every year is appropriate. In follow-up, chest CT and abdominal ultrasonography should be implemented. Cranial MRI should be performed every half year for patients with adenocarcinoma. Bone scan should be undertaken every year for all patients.

Primary Endpoint: Rate of radiation-induced pneumonitis, esophagitis, myelosuppression (CTCAE V4.0).

Secondary Endpoint: 1-year local-regional control rate, 1-year progression-free survival rate, 1-year overall survival rate (RECIST v1.1).

There are two parallel group with each of 18 patients. One group would receive high-dose hypofraction radiotherapy of 60-68Gy/15-17f and the other group would receive low-dose hypofraction radiotherapy of 48Gy/12f.

Hypofraction Radiotherapy for Locally Advanced Non-small Cell Lung Cancer

Hypofraction Radiotherapy Followed by Immune Checkpoint Inhibitors for Locally Advanced Non-small Cell Lung Cancer: A Phase I/II Trial

Rate of radiation-induced pneumonitis (CTCAE V4.0)

Rate of radiation-induced esophagitis (CTCAE V4.0)

1 year locoregional control rate (RECIST 1.1)

1 year progression-free rate (RECIST 1.1)

1 year overall survival rate (RECIST 1.1)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Organ Preservation Following Enverolimab-based Total Neoadjuvant Therapy for Locally Advanced Very Low Rectal Cancer	NCT05969847	Rectal Cancer	split-course hy... CAPOX Envafolimab Local excision	18 Years - 75 Years	Fujian Medical University Union Hospital
Hypofraction Radiotherapy for Locally Advanced Non-small Cell Lung Cancer	NCT05269485	Toxicity Due to... Non-small Cell ...	High-dose fract... Low-dose fracti...	18 Years - 70 Years	Anhui Provincial Hospital

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