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| ID | Type | Description | Link |
|---|---|---|---|
| iIRB No. A11304001 | Other Identifier | Dalin Tzu Chi Hospital - Research Ethics Committee |
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| Name | Class |
|---|---|
| Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation | UNKNOWN |
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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:
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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| TNT + mEHT | Experimental | Participants receive standard TNT with modulated electro-hyperthermia (mEHT). This includes long-course CRT with concurrent mEHT, twice weekly, for 5-6 weeks, followed by neoadjuvant chemotherapy (4-6 months), and finally surgery. Chemoradiation therapy phase Drug: Capecitabine or Tegafur/ Uracil or Fluorouracil (5-FU) + Leucrorin (LV) concomitant with RT Procedure: Radiotherapy Total radiation dose of 45-50.4 Gy delivered in 25-28 fractions to the pelvis, and the dose of 52-56 Gy for gross tumor volumes and positive lymph nodes. Device: Oncotherm Modulated EHY-2030 Oncotherm device is working on a radiofrequency of 13.56 MHz. Treatments are administered twice weekly during the 5-6-week CRT phase. Each session lasts 60 minutes Neoadjuvant systemic therapy: 4-6 months of neoadjuvant chemotherapy using CAPEOX or mFOLFOX 6 regimens following CRT Surgery: Total mesorectal excision (TME) performed after the completion of neoadjuvant chemotherapy. |
|
| TNT alone | No Intervention | Participants receive standard TNT without modulated electro-hyperthermia (mEHT). This includes long-course CRT with concurrent mEHT, twice weekly, for 5-6 weeks, followed by neoadjuvant chemotherapy (4-6 months), and finally surgery. Chemoradiation therapy phase Drug: Capecitabine or Tegafur/ Uracil or Fluorouracil (5-FU) + Leucrorin (LV) concomitant with RT Procedure: Radiotherapy Total radiation dose of 45-50.4 Gy delivered in 25-28 fractions to the pelvis, and the dose of 52-56 Gy for gross tumor volumes and positive lymph nodes. Device: Oncotherm Modulated EHY-2030 Neoadjuvant systemic therapy: 4-6 months of neoadjuvant chemotherapy using CAPEOX or mFOLFOX 6 regimens following CRT Surgery: Total mesorectal excision (TME) performed after the completion of neoadjuvant chemotherapy. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Hyperthermia | Device | Modulated electro-hyperthermia, 2 times weekly for 6 weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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: 9 months from the date of randomization |
| Measure | Description | Time Frame |
|---|---|---|
| Pathological Complete Response (pCR) Rate. | A pCR must include no gross or microscopic tumor identified anywhere within the surgical specimen. This must include:
| 9 months from the date of randomization |
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Inclusion Criteria:
Age: 20 years and above
Gender: Not restricted
Initial pathological diagnosis of adenocarcinoma of the rectum
Expected survival ≥ six months
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]:
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:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Pei-Yu Hsu, Master | Contact | +886+5+2648000 | 5668 | dorishsu1071013@gmail.com |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dalin Tzu Chi Hospital | Recruiting | Chiayi City | Dalin Township | 600401 | Taiwan |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35483010 | Background | Garcia-Aguilar J, Patil S, Gollub MJ, Kim JK, Yuval JB, Thompson HM, Verheij FS, Omer DM, Lee M, Dunne RF, Marcet J, Cataldo P, Polite B, Herzig DO, Liska D, Oommen S, Friel CM, Ternent C, Coveler AL, Hunt S, Gregory A, Varma MG, Bello BL, Carmichael JC, Krauss J, Gleisner A, Paty PB, Weiser MR, Nash GM, Pappou E, Guillem JG, Temple L, Wei IH, Widmar M, Lin S, Segal NH, Cercek A, Yaeger R, Smith JJ, Goodman KA, Wu AJ, Saltz LB. Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy. J Clin Oncol. 2022 Aug 10;40(23):2546-2556. doi: 10.1200/JCO.22.00032. Epub 2022 Apr 28. | |
| 21328328 |
| Label | URL |
|---|---|
| Network NCC. Rectal Cancer (Version 2.2024). | View source |
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| ID | Term |
|---|---|
| D012004 | Rectal Neoplasms |
| D000084462 | Hyperthermia |
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
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| ID | Term |
|---|---|
| D003972 | Diathermy |
| ID | Term |
|---|---|
| D006979 | Hyperthermia, Induced |
| D013812 | Therapeutics |
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| Treatment Response Patterns |
Using the Dworak Scale, defined as "good tumor shrinkage" with Grade 3 and Grade 4. |
| 9 months |
| Overall Survival (OS) | OS is defined as time from randomization to the date of death due to any cause. | 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. | 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: 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. | 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. | 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. | 12 months |
| Surgical Techniques | Surgical Techniques to be recorded: Total Mesorectal Excision (TME), local excision or other (specify). | 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. | 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). | 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). | 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). | 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). | 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. | 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:
| 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:
| 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:
| 12 months |
| Background |
| Park JH, Yoon SM, Yu CS, Kim JH, Kim TW, Kim JC. Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer. Cancer. 2011 Aug 15;117(16):3703-12. doi: 10.1002/cncr.25943. Epub 2011 Feb 15. |
| 22504191 | Background | Emmertsen KJ, Laurberg S. Low anterior resection syndrome score: development and validation of a symptom-based scoring system for bowel dysfunction after low anterior resection for rectal cancer. Ann Surg. 2012 May;255(5):922-8. doi: 10.1097/SLA.0b013e31824f1c21. |
| 29606101 | Background | Shen MH, Chen LP, Ho TF, Shih YY, Huang CS, Chie WC, Huang CC. Validation of the Taiwan Chinese version of the EORTC QLQ-CR29 to assess quality of life in colorectal cancer patients. BMC Cancer. 2018 Apr 2;18(1):353. doi: 10.1186/s12885-018-4312-y. |
| 7713774 | Background | Rubin P, Constine LS, Fajardo LF, Phillips TL, Wasserman TH. RTOG Late Effects Working Group. Overview. Late Effects of Normal Tissues (LENT) scoring system. Int J Radiat Oncol Biol Phys. 1995 Mar 30;31(5):1041-2. doi: 10.1016/0360-3016(95)00057-6. No abstract available. |
| 9112145 | Background | Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis. 1997;12(1):19-23. doi: 10.1007/s003840050072. |
| 19588384 | Background | De Haas-Kock DF, Buijsen J, Pijls-Johannesma M, Lutgens L, Lammering G, van Mastrigt GA, De Ruysscher DK, Lambin P, van der Zee J. Concomitant hyperthermia and radiation therapy for treating locally advanced rectal cancer. Cochrane Database Syst Rev. 2009 Jul 8;2009(3):CD006269. doi: 10.1002/14651858.CD006269.pub2. |
| 33987952 | Background | Liu S, Jiang T, Xiao L, Yang S, Liu Q, Gao Y, Chen G, Xiao W. Total Neoadjuvant Therapy (TNT) versus Standard Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis. Oncologist. 2021 Sep;26(9):e1555-e1566. doi: 10.1002/onco.13824. Epub 2021 Jun 7. |
| 33862000 | Background | Conroy T, Bosset JF, Etienne PL, Rio E, Francois E, Mesgouez-Nebout N, Vendrely V, Artignan X, Bouche O, Gargot D, Boige V, Bonichon-Lamichhane N, Louvet C, Morand C, de la Fouchardiere C, Lamfichekh N, Juzyna B, Jouffroy-Zeller C, Rullier E, Marchal F, Gourgou S, Castan F, Borg C; Unicancer Gastrointestinal Group and Partenariat de Recherche en Oncologie Digestive (PRODIGE) Group. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 May;22(5):702-715. doi: 10.1016/S1470-2045(21)00079-6. Epub 2021 Apr 13. |
| 35263150 | Background | Jin J, Tang Y, Hu C, Jiang LM, Jiang J, Li N, Liu WY, Chen SL, Li S, Lu NN, Cai Y, Li YH, Zhu Y, Cheng GH, Zhang HY, Wang X, Zhu SY, Wang J, Li GF, Yang JL, Zhang K, Chi Y, Yang L, Zhou HT, Zhou AP, Zou SM, Fang H, Wang SL, Zhang HZ, Wang XS, Wei LC, Wang WL, Liu SX, Gao YH, Li YX. Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR). J Clin Oncol. 2022 May 20;40(15):1681-1692. doi: 10.1200/JCO.21.01667. Epub 2022 Mar 9. |
| 36661037 | Background | Dijkstra EA, Nilsson PJ, Hospers GAP, Bahadoer RR, Meershoek-Klein Kranenbarg E, Roodvoets AGH, Putter H, Berglund A, Cervantes A, Crolla RMPH, Hendriks MP, Capdevila J, Edhemovic I, Marijnen CAM, van de Velde CJH, Glimelius B, van Etten B; Collaborative Investigators. Locoregional Failure During and After Short-course Radiotherapy Followed by Chemotherapy and Surgery Compared With Long-course Chemoradiotherapy and Surgery: A 5-Year Follow-up of the RAPIDO Trial. Ann Surg. 2023 Oct 1;278(4):e766-e772. doi: 10.1097/SLA.0000000000005799. Epub 2023 Jan 20. |
| 33301740 | Background | Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, Roodvoets AGH, Nagtegaal ID, Beets-Tan RGH, Blomqvist LK, Fokstuen T, Ten Tije AJ, Capdevila J, Hendriks MP, Edhemovic I, Cervantes A, Nilsson PJ, Glimelius B, van de Velde CJH, Hospers GAP; RAPIDO collaborative investigators. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jan;22(1):29-42. doi: 10.1016/S1470-2045(20)30555-6. Epub 2020 Dec 7. |
| 22473163 | Background | Dewdney A, Cunningham D, Tabernero J, Capdevila J, Glimelius B, Cervantes A, Tait D, Brown G, Wotherspoon A, Gonzalez de Castro D, Chua YJ, Wong R, Barbachano Y, Oates J, Chau I. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C). J Clin Oncol. 2012 May 10;30(14):1620-7. doi: 10.1200/JCO.2011.39.6036. Epub 2012 Apr 2. |
| 28560805 | Background | Ma B, Gao P, Wang H, Xu Q, Song Y, Huang X, Sun J, Zhao J, Luo J, Sun Y, Wang Z. What has preoperative radio(chemo)therapy brought to localized rectal cancer patients in terms of perioperative and long-term outcomes over the past decades? A systematic review and meta-analysis based on 41,121 patients. Int J Cancer. 2017 Sep 1;141(5):1052-1065. doi: 10.1002/ijc.30805. Epub 2017 Jun 8. |
| 19770376 | Background | Roh MS, Colangelo LH, O'Connell MJ, Yothers G, Deutsch M, Allegra CJ, Kahlenberg MS, Baez-Diaz L, Ursiny CS, Petrelli NJ, Wolmark N. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009 Nov 1;27(31):5124-30. doi: 10.1200/JCO.2009.22.0467. Epub 2009 Sep 21. |
| 19269519 | Background | Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R, Khanna S, Quirke P, Couture J, de Metz C, Myint AS, Bessell E, Griffiths G, Thompson LC, Parmar M. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet. 2009 Mar 7;373(9666):811-20. doi: 10.1016/S0140-6736(09)60484-0. |
| 33097436 | Background | Wo JY, Anker CJ, Ashman JB, Bhadkamkar NA, Bradfield L, Chang DT, Dorth J, Garcia-Aguilar J, Goff D, Jacqmin D, Kelly P, Newman NB, Olsen J, Raldow AC, Ruiz-Garcia E, Stitzenberg KB, Thomas CR Jr, Wu QJ, Das P. Radiation Therapy for Rectal Cancer: Executive Summary of an ASTRO Clinical Practice Guideline. Pract Radiat Oncol. 2021 Jan-Feb;11(1):13-25. doi: 10.1016/j.prro.2020.08.004. Epub 2020 Oct 21. |
| 15496622 | Background | Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004 Oct 21;351(17):1731-40. doi: 10.1056/NEJMoa040694. |
| 22529255 | Background | Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, Wittekind C, Beissbarth T, Rodel C. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012 Jun 1;30(16):1926-33. doi: 10.1200/JCO.2011.40.1836. Epub 2012 Apr 23. |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| D001832 | Body Temperature Changes |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D018882 | Heat Stress Disorders |
| D014947 | Wounds and Injuries |