Modulated Electro-Hyperthermia in Combination With Multimodal Therapy for Locally Advanced Rectal Cancer

Phase 3RecruitingNCT07372300

Shih-Kai Hung126 enrolled

Overview

The goal of this clinical trial is to investigate if the addition of modulated electro-hyperthermia (mEHT) improves tumor down-staging and pathological response in adult patients (20 years and above) with locally advanced rectal adenocarcinoma (cT3N0M0 with high risk of recurrence, cT3N1-2M0, or cT4N0-2M0). The main questions it aims to answer are: * Does the addition of mEHT to the Total Neoadjuvant Therapy (TNT) regimen significantly increase the rate of tumor down-staging (ypT and ypN) compared to TNT alone? * Does the combination therapy improve the pathological complete response (pCR) rate and long-term outcomes (such as disease-free survival) compared to standard TNT? Researchers will compare participants randomized to receive Total Neoadjuvant Therapy (TNT) plus mEHT using the Oncotherm EHY-2030 device to participants receiving TNT alone to see if the adjunctive mEHT therapy enhances tumor regression and improves patient prognosis. Participants will be randomized (1:1) into one of the two groups and will undergo the following regimen: * Receive standard TNT, which includes 5-6 weeks of chemoradiotherapy (CRT) followed by 4-6 months of neoadjuvant chemotherapy. * Patients in the experimental group will receive mEHT twice a week during the CRT period.

This study is designed as a pivotal Phase 3, open-label, two-treatment group, multi-institute randomized control trial (1:1). Study Population \& Allocation: Participants with pathologically confirmed rectal adenocarcinoma who are recommended for TNT by a specialist surgeon will be included. Patients are randomly allocated (1:1) into either the Experimental Arm (TNT + mEHT combination) or the Control Arm (TNT alone). Intervention and Device: Modulated electro-hyperthermia (mEHT, trade name Oncotherm) will be delivered using the Oncotherm EHY-2030 device. This technique uses electromagnetic waves at 13.56 MHz and incorporates a low-frequency current wave to deliver energy selectively to the cancerous area. The Oncotherm computer system automatically adjusts the optimal frequency, introducing random resonance to heat the tumor tissue and improve the tumor microenvironment. Local hyperthermia is intended to control tumors by raising the local body temperature to 39℃-42℃. We hypothesized that the combination of hyperthermia with other treatments (such as radiotherapy and chemotherapy) can improve treatment outcome without additional toxicity. Patients in the Experimental Arm will receive mEHT twice a week specifically during the CRT period.

Study Type

INTERVENTIONAL

Eligibility

Sex: ALLMin age: 20 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age: 20 years and above 2. Gender: Not restricted 3. Initial pathological diagnosis of adenocarcinoma of the rectum 4. Expected survival ≥ six months 5. Clinical staging of cT3N0 with high recurrence risk or cT3N1-2 or cT4N0-2 rectal cancer, requiring neoadjuvant therapy, without distant metastasis; must meet the following tumor definitions \[staging system according to the 8th edition of the AJCC staging manual\]: 1. cT3: Tumor invades through the muscularis propria into pericolorectal tissues 2. cT4a: Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum) 3. cT4b: Tumor directly invades or adheres to adjacent organs or structures \*High recurrence risk factors: cT3 tumor ≤ 5 cm from the anal verge or MRI showing circumferential resection margin (CRM) \< 0.2 cm; cT4 tumor or cN2, presence of MRI showing extramural vascular invasion. 7\. ECOG performance status: 0 - 2 8. Healthy condition suitable for standard treatment, including 25 to 30 fractions of long-course radiotherapy and concurrent chemotherapy (capecitabine or fluorouracil) and subsequent 4- to 6-month chemotherapy, including modified FOLFOX-6 or CAPEOX 9. Willingness to participate in the clinical trial and signed the informed consent form for the protocol. Exclusion Criteria: * (e) Active infection or severe underlying disease making the patient unsuitable for the trial treatments * Known HIV infection * Untreated thyroid disease * Active Crohn's disease or ulcerative colitis * Other systemic autoimmune diseases 9. History of any physical or mental disorder resulting the patient unable to understand or comply with trial requirements, or diminished social communication ability, or unable to provide informed consent 10. Known allergic reaction to trial medications 11. Pregnant or breastfeeding women 12. Substance or alcohol dependence within six months before screening 13. Inability to comply with treatment, assessments, or follow-up

Outcomes

Primary Outcomes

Down-staging Rate

Evaluation of the decrease in ypT and ypN staging for patients with locally advanced rectal cancer following the current recommended treatment method, total neoadjuvant therapy (TNT). The ycT and ycN staging will be assessed using MRI within three months post-treatment for patients who do not undergo surgery.

Time frame: Time Frame: 9 months from the date of randomization

Secondary Outcomes

Pathological Complete Response (pCR) Rate.

A pCR must include no gross or microscopic tumor identified anywhere within the surgical specimen. This must include: * No evidence of malignant cells in the primary tumor specimen AND * No evidence of malignant cells in the lymph nodes.

Time frame: 9 months from the date of randomization

Treatment Response Patterns

Using the Dworak Scale, defined as "good tumor shrinkage" with Grade 3 and Grade 4.

Time frame: 9 months

Overall Survival (OS)

OS is defined as time from randomization to the date of death due to any cause.

Time frame: 12, 36, 60 months from the date of randomization

Disease-Free Survival (DFS)

DFS is defined as the time from randomization to the date of local recurrence, regional recurrence, distant recurrence or death due to all causes whichever comes first. Patients who fail to return for evaluation after beginning therapy will be censored for DFS on the last day of therapy.

Time frame: 12, 36, 60 months from the date of randomization

Local Control Rate (LCR)

LCR is defined as the time from randomization to the date of the first documentation of local recurrence.

Time frame: Time Frame: 12, 36, 60 months from the date of randomization.

Distant Metastasis-Free Survival (DMFS)

DMFS is defined as the time from randomization to the date of the first documentation of distant metastasis.

Time frame: 12, 36, 60 months from the date of randomization

Colostomy-Free Survival (CFS)

CFS is defined as being alive without a colostomy, excluding colostomies reversed during follow-up.

Time frame: 12, 36, 60 months from the date of randomization.

Comparison of Surgery Rates

Comparison of Surgery Rates is defined as the rate of patients who receive TME between two groups after TNT.

Time frame: 12 months

Surgical Techniques

Surgical Techniques to be recorded: Total Mesorectal Excision (TME), local excision or other (specify).

Time frame: 12 months

Number of Hyperhermia

For the optimal treatment, patients in experimental arm receive hyperthermia by using Oncotherm EHY-2030 device, with a planned power output of 60 minutes. The number of treatment where this optimal output could not be reached must be recorded and reported.

Time frame: 9 months

Adverse Effects Assessment

Using CTCAE v5.0, scored 0 - 5, with higher scores indicating more severe adverse effects. The items include: radiation dermatitis, anorexia, nausea, vomiting, constipation, diarrhea, dysuria, hematuria, and fatigue. All items are planned to be evaluated at the initiation of treatment (week 1), and subsequently at the week 6, week 9, week 28, week 42, week 48, week 60, week 72, week 84, and week 96 (+/- 3 weeks is permitted).

Time frame: 2, 36, 60 months

The effect of treatment on white blood cell count

Recording total white cell counts, absolute neutrophil counts, and absolute lymphocyte counts of all patients. Blood samples are obtained at the initiation of treatment (week 1), and subsequently at the week 6, week 9, week 28, week 42, week 48, week 60, week 72, week 84, and week 96 (+/- 3 weeks is permitted).

Time frame: 2, 36, 60 months

The effect of treatment on hemoglobin level

Recording hemoglobin levels of all patients. Blood samples are obtained at the initiation of treatment (week 1), and subsequently at the week 6, week 9, week 28, week 42, week 48, week 60, week 72, week 84, and week 96 (+/- 3 weeks is permitted).

Time frame: 2, 36, 60 months

The effect of treatment on platelet count

Recording platelet counts of all patients. Blood samples are obtained at the initiation of treatment (week 1), and subsequently at the week 6, week 9, week 28, week 42, week 48, week 60, week 72, week 84, and week 96 (+/- 3 weeks is permitted).

Time frame: 2, 36, 60 months

Late Radiation Therapy Adverse Effects

Using the LENT/SOMA scoring system, evaluating symptoms such as tenesmus, mucosal loss, sphincter control, stool frequency, pain, bleeding, ulceration, stricture, etc., scored 1 - 4, with higher scores indicating worse outcomes.

Time frame: 36, 60 months

Quality of Life Analysis

Quality of Life (QoL) assessment is mandatory for all eligible patients randomized into the trial. QoL will be evaluated using the total score of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). A printed questionnaire will be administered in the clinic by a CRA or study nurse at the following time points: * Baseline (at the time of randomization, prior to treatment initiation). * The last week of neoadjuvant CRT with or without mEHT. * Nine months after the completion of the TNT course (approximately 42 weeks ± 3 weeks post-randomization).

Time frame: 12 months.

Rectal Cancer Quality of Life Analysis

Rectal Cancer Quality of Life (QoL) assessment is mandatory for all eligible patients randomized into the trial. QoL will be evaluated using the total score of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-CR29). A printed questionnaire will be administered in the clinic by a CRA or study nurse at the following time points: * Baseline (at the time of randomization, prior to treatment initiation). * The last week of neoadjuvant CRT with or without mEHT. * Nine months after the completion of the TNT course (approximately 42 weeks ± 3 weeks post-randomization).

Time frame: 12 months.

Functional Assessment Post Rectal Cancer Surgery

Using the LAR score. The QoL evaluation focus on functional outcome will be evaluated using LAR score. This assessment is mandatory for all eligible patients randomized into the trial. A printed questionnaire will be administered in the clinic by a CRA or study nurse at the following time points: * Baseline (at the time of randomization, prior to treatment initiation). * The last week of neoadjuvant CRT with or without mEHT. * Nine months after the completion of the TNT course (approximately 42 weeks ± 3 weeks post-randomization).

Time frame: 12 months

Modulated Electro-Hyperthermia in Combination With Multimodal Therapy for Locally Advanced Rectal Cancer

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts