Neoadjuvant Chemoradiotherapy Versus Neoadjuvant Chemotherapy For Unresectable Locally Advanced Colon Cancer

Colon Cancer Clinical Trial

Official title:

Neoadjuvant Chemoradiotherapy Versus Neoadjuvant Chemotherapy For Unresectable Locally Advanced Colon Cancer: An Open, Multi-centered, Randomize Controlled Phase 3 Trial.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03970694
• Other study ID #: 2018-FXY-194
• Status: Terminated
• Phase: Phase 3
• Start date: May 11, 2019
• Est. completion date: June 5, 2022

Study information

• Verified date: June 2022
• Source: Sun Yat-sen University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A. Background and purpose: Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for unresectable locally advanced colon cancer: an open, multi-centered, randomize controlled phase 3 trial. Colorectal cancer is one of the most common malignant tumors, the morbidity and mortality rate are both in rising trend. 10-23% newly diagnosed colon cancer is at locally advanced stage and surgically unresectable. For this subgroup, treatment guidelines recommend neoadjuvant chemotherapy with or without targeted therapy. However, less than 50% patients could convert into R0 resectable, therapeutic effect is unsatisfactory, 5-year overall survival rate is only 12.5%-45.7%.[JCO,2010] Since 2006, neoadjuvant chemoradiotherapy has been a recommendation as standard treatment for locally advanced rectal cancer, and has been widely applied to clinical use. As for locally advanced colon cancer, it still lacks evidence to support whether neoadjuvant chemoradiotherapy is a beneficial option. There are only several articles about locally advanced colon cancer undertaking neoadjuvant chemoradiotherapy before surgery through Pubmed research, including 3 case reports, 1 abstract and 5 clinical researches with a small sample size, 3 of which are from the investigator's study group. The investigators recently reported clinical data about therapeutic effect of 60 unresectable locally advanced colon cancer cases and the results were exciting. According to the results, through neoadjuvant chemoradiotherapy, R0 resection rate is 86%, local recurrence rate is 10.2%, 3-year OS and 5-year OS are 76.7% and 66.6%, respectively. [Onco Targets Ther, 2018] "Colorectal cancer diagnoses and treatment guidelines" written by Chinses Society of Clinical Oncology (ver. 2017, 2018), suggested that neoadjuvant chemoradiotherapy was an optional treatment strategy or secondary recommended treatment strategy. In a word, the investigators' result was referred as revisory basis of the guideline [CJC,2016], with a relatively low level of evidence in evidence-based medicine. This phase 3 clinical trial mainly aims to acquire a higher level of evidence in evidence-based medicine on the subject about neoadjuvant chemoradiotherapy as a treatment strategy to unresectable locally advanced colon cancer, and the ultimate goal is to rewrite the International treatment guidelines of locally advanced colorectal cancer. B. Research Content: 1. . Research Object: Patients who newly diagnosed unresectable locally advanced colon cancer. Including: 1. tumor infiltrates through the intestinal wall and adheres to tissues and organs around the colon(T4b), imaging assesses that R0 resection is unachievable. 2. Pericolonic lymph node involvement is closely adjacent to the large abdominal vessels, imaging assesses that lymphadenectomy is difficult. 3. Surgical exploration indicates that R0 resection is not achievable. 4. In initial diagnosis, surgeon evaluates the need for extensive multi-organ combined resection and expected to damage the organs, which would seriously affect the postoperative quality of life. 2. . Main research indicator: 5-year overall survival rate 3. . Secondary research indicators: 1. R0 resection rate 2. 3-year tumor-free survival rate 4. . Research groups assignment: 1. Research group: Neoadjuvant chemoradiotherapy group; 2. Control group: Neoadjuvant chemotherapy group. 5. . Sample calculation: Calculation is based on the main research indicator: 5-year survival rate. Based on α=0.05(bilateral), β=0.20(unilateral), 5-year OS improves from 45% in control group to 65% in research group, 4-year period, 5-year follow-up. Research group and control group should at least enroll 74 and 75 qualified cases, respectively, a total of 149 cases, with an expected delisting rate of 20%, the total sample size is 186, 93 cases for each group. 6. . Research protocols: 1. Research group: Neoadjuvant chemoradiotherapy（XELOX * 4 + radiotherapy）→ Surgery (if possible) → post-surgery chemotherapy. 2. Control group: Neoadjuvant chemotherapy（XELOX * 4）→ Surgery (if possible) → post-surgery chemotherapy. Chemotherapy strategy: XELOX: oxaliplatin 130mg/m2, iv drip, d1, every 3 weeks; capecitabine 1,000mg/m2, bid, d1-d14, every 3 weeks. Concurrent chemotherapy: mXELOX: which oxaliplatin is 100mg/m2. Radiotherapy strategy: IMRT, 6-8MV X-ray; GTV 45-50Gy/25F, 1.8-2.0Gy/F; CTV 42.5-45Gy/25F, 1.7-1.8Gy/F; Actual delivery dose should be adjusted according to max tolerance dose of organs at risk, but the delivery dose of GTV and CTV must within the required range. Surgery: Reexamination is performed 5 weeks after radiotherapy for research group and 2 weeks after the fourth period of chemotherapy, surgery is performed in 6-12 weeks after neoadjuvant treatment.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 49
• Est. completion date: June 5, 2022
• Est. primary completion date: May 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Histology confirms colonic adenocarcinoma.
• The distance from the lower edge of the tumor to the anal edge is greater than or equal to 15cm (from sigmoid colon to ileocecal region)
• Preoperative staging (Satisfying any one out of four conditions below)

1. Tumor infiltrates through the intestinal wall and adheres to tissues and organs around the colon(T4b), imaging assesses that R0 resection is unachievable.

2. Pericolonic lymph node involvement is closely adjacent to the large abdominal vessels, imaging assesses that lymphadenectomy is difficult.

3. Surgical exploration indicates that R0 resection is not achievable.

4. In initial diagnosis, surgeon evaluates the need for extensive multi-organ combined resection and expected to damage the organs, which would seriously affect the postoperative quality of life.

• No obvious signs of intestinal obstruction, or obstruction has been relieved after proximal enterostomy.
• Preoperative CT/MRI/PET-CT has ruled out distant metastasis.
• Blood and biochemical indexes achieve standard (Satisfying all three conditions

below):

1. Routine blood test: WBC>4000/mm3; PLT>100000/mm3; Hb>6g/dl.

2. Liver function: SGOT, SGPT and Bilirubin are less than or equal to 1.5 times normal upper limit.

3. Renal function: Creatinine is less than or equal to 1.5 times normal upper limit.

Exclusion Criteria:

• History: Has colon surgery history; Received chemotherapy or biotherapy in the past 5 years; Received radiotherapy in treatment field.
• Infectious disease: HIV infection history; Active phase chronic hepatitis B or hepatitis C (high copies of virus DNA); Other serious active clinical infection.
• Diagnosed as stage I colon cancer.
• Extraperitoneal distant metastasis is positive in pre-operative stage.
• Dyscrasia or organ decompensation.
• Received radiation therapy in abdominal or pelvic regions.
• Multiple primary cancer.
• Epileptic seizures requiring medical treatment.
• Other malignant tumor history in the past 5 years (except endocervical cancer in situ or skin basal cell carcinoma which had been cured)
• Chronic inflammatory colorectal disease, unrelieved ileus.
• Drug abuse, has medical, psychological or social condition that might affect research results.
• Allergic to research-related drugs.
• Any unstable situation that might endanger patient's safety or compliance.
• Pregnant, lactating woman patient or fertile but lacks adequate contraceptives.
• Refuses to sign informed consent.

Related Conditions & MeSH terms

• Colon Cancer
• Colonic Neoplasms

Intervention

Radiation:
• Radiotherapy
Since 2006, neoadjuvant chemoradiotherapy has been a recommendation as standard treatment for locally advanced rectal cancer, and has been widely applied to clinical use. As for locally advanced colon cancer, it still lacks evidence to support whether neoadjuvant chemoradiotherapy is a beneficial option.We recently reported clinical data about therapeutic effect of 60 unresectable locally advanced colon cancer cases and it was exciting. According to our results, through neoadjuvant chemoradiotherapy, R0 resection rate is 86%, local recurrence rate is 10.2%, 3-year OS and 5-year OS are 76.7% and 66.6%, respectively."Colorectal cancer diagnoses and treatment guidelines" written by Chinses Society of Clinical Oncology (ver. 2017, 2018), suggested that neoadjuvant chemoradiotherapy was an optional treatment strategy or secondary recommended treatment strategy.

Drug:
• oxaliplatin+capecitabine
Colorectal cancer is one of the most common malignant tumors, the morbidity and mortality rate are both in rising trend. 10-23% newly diagnosed colon cancer is at locally advanced stage and surgical unresectable. For this subgroup, treatment guidelines recommend neoadjuvant chemotherapy with or without targeted therapy.

Locations

Country	Name	City	State
China	Sun Yat-sen University Cancer Center	Guangzhou	Guangdong

Sponsors (7)

Lead Sponsor	Collaborator
Sun Yat-sen University	First Affiliated Hospital, Sun Yat-Sen University, Fujian Medical University Union Hospital, Nanfang Hospital of Southern Medical University, Second Affiliated Hospital, School of Medicine, Zhejiang University, Sixth Affiliated Hospital, Sun Yat-sen University, Tongji Hospital

Country where clinical trial is conducted

China, 

References & Publications (30)

Arredondo J, González I, Baixauli J, Martínez P, Rodríguez J, Pastor C, Ribelles MJ, Sola JJ, Hernández-Lizoain JL. Tumor response assessment in locally advanced colon cancer after neoadjuvant chemotherapy. J Gastrointest Oncol. 2014 Apr;5(2):104-11. doi: 10.3978/j.issn.2078-6891.2014.006. — View Citation

Arredondo J, Pastor C, Baixauli J, Rodríguez J, González I, Vigil C, Chopitea A, Hernández-Lizoáin JL. Preliminary outcome of a treatment strategy based on perioperative chemotherapy and surgery in patients with locally advanced colon cancer. Colorectal Dis. 2013 May;15(5):552-7. doi: 10.1111/codi.12119. — View Citation

Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC; EORTC Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006 Sep 14;355(11):1114-23. Erratum in: N Engl J Med. 2007 Aug 16;357(7):728. — View Citation

Burton S, Brown G, Daniels I, Norman A, Swift I, Abulafi M, Wotherspoon A, Tait D. MRI identified prognostic features of tumors in distal sigmoid, rectosigmoid, and upper rectum: treatment with radiotherapy and chemotherapy. Int J Radiat Oncol Biol Phys. 2006 Jun 1;65(2):445-51. — View Citation

Chang H, Yu X, Xiao WW, Wang QX, Zhou WH, Zeng ZF, Ding PR, Li LR, Gao YH. Neoadjuvant chemoradiotherapy followed by surgery in patients with unresectable locally advanced colon cancer: a prospective observational study. Onco Targets Ther. 2018 Jan 17;11:409-418. doi: 10.2147/OTT.S150367. eCollection 2018. — View Citation

Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016 Mar-Apr;66(2):115-32. doi: 10.3322/caac.21338. Epub 2016 Jan 25. — View Citation

Croner RS, Merkel S, Papadopoulos T, Schellerer V, Hohenberger W, Goehl J. Multivisceral resection for colon carcinoma. Dis Colon Rectum. 2009 Aug;52(8):1381-6. doi: 10.1007/DCR.0b013e3181ab580b. — View Citation

Cukier M, Smith AJ, Milot L, Chu W, Chung H, Fenech D, Herschorn S, Ko Y, Rowsell C, Soliman H, Ung YC, Wong CS. Neoadjuvant chemoradiotherapy and multivisceral resection for primary locally advanced adherent colon cancer: a single institution experience. Eur J Surg Oncol. 2012 Aug;38(8):677-82. doi: 10.1016/j.ejso.2012.05.001. Epub 2012 May 24. — View Citation

Curley SA, Carlson GW, Shumate CR, Wishnow KI, Ames FC. Extended resection for locally advanced colorectal carcinoma. Am J Surg. 1992 Jun;163(6):553-9. — View Citation

de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, Cunningham D, Cartwright TH, Hecht JR, Rivera F, Im SA, Bodoky G, Salazar R, Maindrault-Goebel F, Shacham-Shmueli E, Bajetta E, Makrutzki M, Shang A, André T, Hoff PM. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012 Dec;13(12):1225-33. doi: 10.1016/S1470-2045(12)70509-0. Epub 2012 Nov 16. — View Citation

Eldar S, Kemeny MM, Terz JJ. Extended resections for carcinoma of the colon and rectum. Surg Gynecol Obstet. 1985 Oct;161(4):319-22. — View Citation

Foxtrot Collaborative Group. Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial. Lancet Oncol. 2012 Nov;13(11):1152-60. doi: 10.1016/S1470-2045(12)70348-0. Epub 2012 Sep 25. — View Citation

Gérard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin MT, Untereiner M, Leduc B, Francois E, Maurel J, Seitz JF, Buecher B, Mackiewicz R, Ducreux M, Bedenne L. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006 Oct 1;24(28):4620-5. — View Citation

Govindarajan A, Coburn NG, Kiss A, Rabeneck L, Smith AJ, Law CH. Population-based assessment of the surgical management of locally advanced colorectal cancer. J Natl Cancer Inst. 2006 Oct 18;98(20):1474-81. — View Citation

Hallet J, Zih FS, Lemke M, Milot L, Smith AJ, Wong CS. Neo-adjuvant chemoradiotherapy and multivisceral resection to optimize R0 resection of locally recurrent adherent colon cancer. Eur J Surg Oncol. 2014 Jun;40(6):706-12. doi: 10.1016/j.ejso.2014.01.009. Epub 2014 Feb 2. — View Citation

Karoui M, Koubaa W, Delbaldo C, Charachon A, Laurent A, Piedbois P, Cherqui D, Tran Van Nhieu J. Chemotherapy has also an effect on primary tumor in colon carcinoma. Ann Surg Oncol. 2008 Dec;15(12):3440-6. doi: 10.1245/s10434-008-0167-9. Epub 2008 Oct 11. — View Citation

Kuga Y, Tanaka T, Arita M, Okanobu H, Miwata T, Yoshimi S, Murakami E, Numata Y, Moriya T, Ohya T, Nishida T. [A case of effective chemotherapy using S-1 and CPT-11 following chemoradiotherapy with UFT and Leucovorin for unresectable advanced sigmoid colon cancer]. Gan To Kagaku Ryoho. 2010 Mar;37(3):531-4. Japanese. — View Citation

Lehnert T, Methner M, Pollok A, Schaible A, Hinz U, Herfarth C. Multivisceral resection for locally advanced primary colon and rectal cancer: an analysis of prognostic factors in 201 patients. Ann Surg. 2002 Feb;235(2):217-25. — View Citation

Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. doi: 10.1056/NEJMoa1403108. — View Citation

Masi G, Loupakis F, Salvatore L, Fornaro L, Cremolini C, Cupini S, Ciarlo A, Del Monte F, Cortesi E, Amoroso D, Granetto C, Fontanini G, Sensi E, Lupi C, Andreuccetti M, Falcone A. Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol. 2010 Sep;11(9):845-52. doi: 10.1016/S1470-2045(10)70175-3. Epub 2010 Aug 9. — View Citation

O'Neill B, Brown G, Wotherspoon A, Burton S, Norman A, Tait D. Successful downstaging of high rectal and recto-sigmoid cancer by neo-adjuvant chemo-radiotherapy. Clin Med Oncol. 2008;2:135-44. Epub 2008 Mar 1. — View Citation

Qiu B, Ding PR, Cai L, Xiao WW, Zeng ZF, Chen G, Lu ZH, Li LR, Wu XJ, Mirimanoff RO, Pan ZZ, Xu RH, Gao YH. Outcomes of preoperative chemoradiotherapy followed by surgery in patients with unresectable locally advanced sigmoid colon cancer. Chin J Cancer. 2016 Jul 7;35(1):65. doi: 10.1186/s40880-016-0126-y. — View Citation

Reibetanz J, Germer CT. [Neoadjuvant chemotherapy for locally advanced colon cancer : Initial results of the FOxTROT study.]. Chirurg. 2013 Oct 13. [Epub ahead of print] German. — View Citation

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. — View Citation

Sauer R, Becker H, Hohenberger W, Rödel 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. — View Citation

Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Petersen LN, Blons H, Collette L, Van Cutsem E, Rougier P, Salazar R, Bedenne L, Emile JF, Laurent-Puig P, Lepage C; PETACC-8 Study Investigators. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Jul;15(8):862-73. doi: 10.1016/S1470-2045(14)70227-X. Epub 2014 Jun 11. — View Citation

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015 Mar;65(2):87-108. doi: 10.3322/caac.21262. Epub 2015 Feb 4. — View Citation

Yamada Y, Takahari D, Matsumoto H, Baba H, Nakamura M, Yoshida K, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1278-86. doi: 10.1016/S1470-2045(13)70490-X. Epub 2013 Nov 11. Erratum in: Lancet Oncol. 2014 Jan;15(1):e4. — View Citation

Yoh T, Yamamichi K, Oishi M, Iwaki R, Motohiro T. [A case of effective neoadjuvant chemoradiotherapy with capecitabine for locally advanced sigmoid colon cancer]. Gan To Kagaku Ryoho. 2011 Jun;38(6):1021-4. Review. Japanese. — View Citation

Yoshitomi M, Hashida H, Nomura A, Ueda S, Terajima H, Osaki N. [A case of locally advanced sigmoid colon cancer treated with neoadjuvant chemoradiotherapy]. Gan To Kagaku Ryoho. 2014 Sep;41(9):1175-8. Japanese. — View Citation

* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	5-year overall survival rate	The percentage of patients survive 5 years after treatment.	5 years after treatment
Secondary	R0 resection rate	The percentage of patients whose post-operative pathology indicate negative margin is observed under microscope	an average of 6 to 12 weeks after surgery
Secondary	3-year progression-free survival rate	The percentage of patients have no tumor progression after treatment.	3 years after treatment