Epidural Anesthesia-analgesia and Long-term Survival After Lung Cancer Surgery

Lung Cancer Clinical Trial

Official title:

Effects of Epidural Anesthesia-analgesia on Long-term Survival in Patients After Lung Cancer Surgery: A Randomized Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02801409
• Other study ID #: 2013[653]
• Secondary ID: ChiCTR-TRC-14004
• Status: Completed
• Phase: N/A
• Start date: May 25, 2015
• Est. completion date: November 30, 2019

Study information

• Verified date: August 2020
• Source: Peking University First Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Available studies suggest that regional anesthesia-analgesia may decrease the occurrence of recurrence/metastasis in patients after cancer surgery. However, evidences from prospective studies are still lacking. The purpose of this randomized controlled trial is to investigate the effect of epidural anesthesia-analgesia on recurrence-free survival in patients undergoing lung cancer surgery.

Description:

Lung cancer is increasing and is the leading cause of cancer death. Surgical resection is the mainstay of treatment for early stage non-small cell lung cancer. However, long-term survival after lung cancer surgery is far from optimal, and cancer recurrence or metastasis is the main reason leading to cancer death in these patients.

The development of cancer recurrence/metastasis largely depends on the balance between tumor-promoting factors and immune function of the body. Studies showed that surgical manipulation releases cancer cells into circulation; and stress response induced by surgery inhibits the cell-mediated immunity. In addition, volatile anesthetics and opioids may also aggravate immunosuppression and potentially worsen long-term outcome. On the other hand, regional anesthesia can blunt surgical stress and reduce anesthetic consumption. These effects may help to preserve immune function and reduce recurrence/metastasis. However, existing evidences are insufficient to draw conclusion in this topic.

The purpose of this randomized controlled trial is to test the hypothesize that regional anesthesia-analgesia may reduce recurrence/metastasis and improve long-term survival in patients after lung cancer surgery.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 400
• Est. completion date: November 30, 2019
• Est. primary completion date: November 11, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Adult patients (aged 18-80 years);

2. Clinically diagnosed as primary non-small cell lung cancer of stage IA to IIIA, and scheduled for radical surgery;

3. Agreed to receive patient-controlled analgesia after surgery.

Exclusion Criteria:

1. Distant metastasis, malignant tumor in other organs, or chemo-/radiotherapy or other anti-cancer therapy before surgery;

2. Comorbid with autoimmune diseases, or glucocorticoid/immunosuppressant therapy within 1 year;

3. History of schizophrenia, epilepsy or Parkinson disease, or unable to complete preoperative assessment due to severe dementia, language barrier, or end-stage disease;

4. Severe hepatic disease (Child-Pugh classification C), renal failure (serum creatinine >442 umol/L or receiving renal replacement therapy), or American Society of Anesthesiologists classification IV or higher;

5. History of anesthesia and/or surgery within 1 year;

6. Contraindications to epidural anesthesia, including spinal deformity, coagulation dysfunction, local infection, and history of spinal trauma/surgery;

7. Allergic to any medications used during the study.

Related Conditions & MeSH terms

• Anesthesia, Epidural
• Lung Cancer
• Lung Neoplasms
• Neoplasm Metastasis
• Neoplasm Recurrence, Local
• Neoplasms
• Recurrence
• Thoracic Surgery

Intervention

Drug:
• General anesthesia alone
General anesthesia is performed during surgery; patient-controlled intravenous analgesia is provided after surgery.
• Combined epidural-general anesthesia
Combined epidural-general anesthesia is performed during surgery; patient-controlled epidural analgesia is provided after surgery.

Locations

Country	Name	City	State
China	Peking University First Hospital	Beijing	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Peking University First Hospital

Country where clinical trial is conducted

China, 

References & Publications (42)

Afsharimani B, Cabot PJ, Parat MO. Morphine use in cancer surgery. Front Pharmacol. 2011 Aug 8;2:46. doi: 10.3389/fphar.2011.00046. eCollection 2011. — View Citation

Ahlers O, Nachtigall I, Lenze J, Goldmann A, Schulte E, Höhne C, Fritz G, Keh D. Intraoperative thoracic epidural anaesthesia attenuates stress-induced immunosuppression in patients undergoing major abdominal surgery. Br J Anaesth. 2008 Dec;101(6):781-7. doi: 10.1093/bja/aen287. Epub 2008 Oct 15. — View Citation

Alberts WM. Follow up and surveillance of the patient with lung cancer: what do you do after surgery? Respirology. 2007 Jan;12(1):16-21. Review. — View Citation

Andersen BL, Farrar WB, Golden-Kreutz D, Kutz LA, MacCallum R, Courtney ME, Glaser R. Stress and immune responses after surgical treatment for regional breast cancer. J Natl Cancer Inst. 1998 Jan 7;90(1):30-6. — View Citation

Biki B, Mascha E, Moriarty DC, Fitzpatrick JM, Sessler DI, Buggy DJ. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology. 2008 Aug;109(2):180-7. doi: 10.1097/ALN.0b013e31817f5b73. — View Citation

Bruzzi JF, Munden RF. PET/CT imaging of lung cancer. J Thorac Imaging. 2006 May;21(2):123-36. Review. — View Citation

Carter JJ, Whelan RL. The immunologic consequences of laparoscopy in oncology. Surg Oncol Clin N Am. 2001 Jul;10(3):655-77. Review. — View Citation

Christopherson R, James KE, Tableman M, Marshall P, Johnson FE. Long-term survival after colon cancer surgery: a variation associated with choice of anesthesia. Anesth Analg. 2008 Jul;107(1):325-32. doi: 10.1213/ane.0b013e3181770f55. — View Citation

Colt HG, Murgu SD, Korst RJ, Slatore CG, Unger M, Quadrelli S. Follow-up and surveillance of the patient with lung cancer after curative-intent therapy: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):e437S-e454S. doi: 10.1378/chest.12-2365. — View Citation

Conrick-Martin I, Buggy DJ. The effects of anesthetic and analgesic techniques on immune function. J Clin Anesth. 2013 Jun;25(4):253-4. doi: 10.1016/j.jclinane.2013.04.003. Epub 2013 Apr 26. — View Citation

Cummings KC 3rd, Xu F, Cummings LC, Cooper GS. A comparison of epidural analgesia and traditional pain management effects on survival and cancer recurrence after colectomy: a population-based study. Anesthesiology. 2012 Apr;116(4):797-806. doi: 10.1097/ALN.0b013e31824674f6. — View Citation

Downing JE, Miyan JA. Neural immunoregulation: emerging roles for nerves in immune homeostasis and disease. Immunol Today. 2000 Jun;21(6):281-9. Review. — View Citation

Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000 Dec;52(4):595-638. Review. — View Citation

Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology. 2006 Oct;105(4):660-4. — View Citation

Freire-Garabal M, Núñez MJ, Balboa JL, Fernández-Rial JC, Vallejo LG, González-Bahillo J, Rey-Méndez M. Effects of alprazolam on cellular immune response to surgical stress in mice. Cancer Lett. 1993 Sep 30;73(2-3):155-60. — View Citation

Gottschalk A, Ford JG, Regelin CC, You J, Mascha EJ, Sessler DI, Durieux ME, Nemergut EC. Association between epidural analgesia and cancer recurrence after colorectal cancer surgery. Anesthesiology. 2010 Jul;113(1):27-34. doi: 10.1097/ALN.0b013e3181de6d0d. — View Citation

Gottschalk A, Sharma S, Ford J, Durieux ME, Tiouririne M. Review article: the role of the perioperative period in recurrence after cancer surgery. Anesth Analg. 2010 Jun 1;110(6):1636-43. doi: 10.1213/ANE.0b013e3181de0ab6. Epub 2010 Apr 30. — View Citation

Gupta A, Björnsson A, Fredriksson M, Hallböök O, Eintrei C. Reduction in mortality after epidural anaesthesia and analgesia in patients undergoing rectal but not colonic cancer surgery: a retrospective analysis of data from 655 patients in central Sweden. Br J Anaesth. 2011 Aug;107(2):164-70. doi: 10.1093/bja/aer100. Epub 2011 May 17. — View Citation

Heaney A, Buggy DJ. Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis? Br J Anaesth. 2012 Dec;109 Suppl 1:i17-i28. doi: 10.1093/bja/aes421. Review. — View Citation

Hofer SO, Molema G, Hermens RA, Wanebo HJ, Reichner JS, Hoekstra HJ. The effect of surgical wounding on tumour development. Eur J Surg Oncol. 1999 Jun;25(3):231-43. Review. — View Citation

Ishihara Y, Matsunaga K, Iijima H, Fujii T, Oguchi Y, Kagawa J. Time-dependent effects of stressor application on metastasis of tumor cells in the lung and its regulation by an immunomodulator in mice. Psychoneuroendocrinology. 1999 Oct;24(7):713-26. — View Citation

Ismail H, Ho KM, Narayan K, Kondalsamy-Chennakesavan S. Effect of neuraxial anaesthesia on tumour progression in cervical cancer patients treated with brachytherapy: a retrospective cohort study. Br J Anaesth. 2010 Aug;105(2):145-9. doi: 10.1093/bja/aeq156. Epub 2010 Jun 23. — View Citation

Kelsey CR, Marks LB, Hollis D, Hubbs JL, Ready NE, D'Amico TA, Boyd JA. Local recurrence after surgery for early stage lung cancer: an 11-year experience with 975 patients. Cancer. 2009 Nov 15;115(22):5218-27. doi: 10.1002/cncr.24625. — View Citation

Klein HG. Immunomodulatory aspects of transfusion: a once and future risk? Anesthesiology. 1999 Sep;91(3):861-5. Review. — View Citation

Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD. Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 2007 Dec 6;450(7171):903-7. Epub 2007 Nov 18. — View Citation

Lai R, Peng Z, Chen D, Wang X, Xing W, Zeng W, Chen M. The effects of anesthetic technique on cancer recurrence in percutaneous radiofrequency ablation of small hepatocellular carcinoma. Anesth Analg. 2012 Feb;114(2):290-6. doi: 10.1213/ANE.0b013e318239c2e3. Epub 2011 Nov 21. Erratum in: Anesth Analg. 2013 Jan;116(1):266. — View Citation

Lennard TW, Shenton BK, Borzotta A, Donnelly PK, White M, Gerrie LM, Proud G, Taylor RM. The influence of surgical operations on components of the human immune system. Br J Surg. 1985 Oct;72(10):771-6. — View Citation

Lin L, Liu C, Tan H, Ouyang H, Zhang Y, Zeng W. Anaesthetic technique may affect prognosis for ovarian serous adenocarcinoma: a retrospective analysis. Br J Anaesth. 2011 Jun;106(6):814-22. doi: 10.1093/bja/aer055. Epub 2011 Mar 24. — View Citation

Myles PS, Peyton P, Silbert B, Hunt J, Rigg JR, Sessler DI; ANZCA Trials Group Investigators. Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: randomised trial. BMJ. 2011 Mar 29;342:d1491. doi: 10.1136/bmj.d1491. — View Citation

Page GG, Blakely WP, Ben-Eliyahu S. Evidence that postoperative pain is a mediator of the tumor-promoting effects of surgery in rats. Pain. 2001 Feb 1;90(1-2):191-9. — View Citation

Pei L, Tan G, Wang L, Guo W, Xiao B, Gao X, Wang L, Li H, Xu Z, Zhang X, Zhao J, Yi J, Huang Y. Comparison of combined general-epidural anesthesia with general anesthesia effects on survival and cancer recurrence: a meta-analysis of retrospective and prospective studies. PLoS One. 2014 Dec 30;9(12):e114667. doi: 10.1371/journal.pone.0114667. eCollection 2014. — View Citation

Piegeler T, Votta-Velis EG, Liu G, Place AT, Schwartz DE, Beck-Schimmer B, Minshall RD, Borgeat A. Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade. Anesthesiology. 2012 Sep;117(3):548-59. — View Citation

Sawyer TE, Bonner JA, Gould PM, Foote RL, Deschamps C, Lange CM, Li H. Factors predicting patterns of recurrence after resection of N1 non-small cell lung carcinoma. Ann Thorac Surg. 1999 Oct;68(4):1171-6. — View Citation

Shakhar G, Ben-Eliyahu S. Potential prophylactic measures against postoperative immunosuppression: could they reduce recurrence rates in oncological patients? Ann Surg Oncol. 2003 Oct;10(8):972-92. Review. — View Citation

Snyder GL, Greenberg S. Effect of anaesthetic technique and other perioperative factors on cancer recurrence. Br J Anaesth. 2010 Aug;105(2):106-15. doi: 10.1093/bja/aeq164. Review. — View Citation

Tashiro T, Yamamori H, Takagi K, Hayashi N, Furukawa K, Nitta H, Toyoda Y, Sano W, Itabashi T, Nishiya K, Hirano J, Nakajima N. Changes in immune function following surgery for esophageal carcinoma. Nutrition. 1999 Oct;15(10):760-6. — View Citation

Taylor MD, Nagji AS, Bhamidipati CM, Theodosakis N, Kozower BD, Lau CL, Jones DR. Tumor recurrence after complete resection for non-small cell lung cancer. Ann Thorac Surg. 2012 Jun;93(6):1813-20; discussion 1820-1. doi: 10.1016/j.athoracsur.2012.03.031. Epub 2012 Apr 26. — View Citation

Tsui BC, Rashiq S, Schopflocher D, Murtha A, Broemling S, Pillay J, Finucane BT. Epidural anesthesia and cancer recurrence rates after radical prostatectomy. Can J Anaesth. 2010 Feb;57(2):107-12. doi: 10.1007/s12630-009-9214-7. — View Citation

Waurick R, Van Aken H. Update in thoracic epidural anaesthesia. Best Pract Res Clin Anaesthesiol. 2005 Jun;19(2):201-13. Review. — View Citation

Wuethrich PY, Hsu Schmitz SF, Kessler TM, Thalmann GN, Studer UE, Stueber F, Burkhard FC. Potential influence of the anesthetic technique used during open radical prostatectomy on prostate cancer-related outcome: a retrospective study. Anesthesiology. 2010 Sep;113(3):570-6. doi: 10.1097/ALN.0b013e3181e4f6ec. — View Citation

Xu YX, Ayala A, Chaudry IH. Prolonged immunodepression after trauma and hemorrhagic shock. J Trauma. 1998 Feb;44(2):335-41. — View Citation

Yamaguchi K, Takagi Y, Aoki S, Futamura M, Saji S. Significant detection of circulating cancer cells in the blood by reverse transcriptase-polymerase chain reaction during colorectal cancer resection. Ann Surg. 2000 Jul;232(1):58-65. — View Citation

* Note: There are 42 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Pain intensity after surgery.	Assessed with the numeric rating score, an 11-point scale where 0 = no pain and 10 = the most severe pain.	During the first 3 days after surgery.
Other	Recurrence-free survival in cancer patients.	Time from surgery to the earliest date of recurrence/metastasis or death from any cause, whichever came first.	Up to 4 years after surgery.
Other	Overall survival in cancer patients.	Time from surgery to all-cause death.	Up to 4 years after surgery.
Other	Cancer-specific survival in cancer patients.	Time from surgery to cancer-specific death; deaths from other causes are censored at the time of death.	Up to 4 years after surgery.
Other	Number of CD8+ and FOXP3+ T cells per mm2 tumor area (sub-study).	Immunohistochemical staining of CD8 and FOXP3 molecules in excised lung adenocarcinoma specimens. Performed in part of enrolled patients.	After resection of lung adenocarcinoma specimens
Other	Percentage of NK-cells and T-cell subgroups in peripheral blood (sub-study).	Measured by flow cytometry. Performed in part of enrolled patients.	Peripheral blood samples collected before induction, at the end of surgery and at 24 hours after surgery.
Other	Rate of chronic pain at 3 month and 6 month after surgery (sub-study).	Chronic pain is measured with the Brief Pain Inventory (BPI), neuropathic pain screening questionnaire (ID pain), and McGill Pain Questionnair (MPQ). Performed in part of enrolled patients.	At 3 months and 6 months after surgery.
Primary	Recurrence-free survival after surgery.	Time from surgery to the earliest date of recurrence/metastasis or death from any cause, whichever came first.	Up to 4 years after surgery.
Secondary	Rate of intensive care unit admission after surgery.	Rate of intensive care unit admission after surgery.	Up to 30 days after surgery.
Secondary	Incidence of postoperative complications during hospital stay.	Postoperative complications are defined as new-onset conditions that are harmful to patients' recovery and required therapeutic intervention, i.e., class II or higher on the Clavien-Dindo classification.	Up to 30 days after surgery.
Secondary	Duration of chest tube placement.	Duration of chest tube placement.	Up to 30 days after surgery.
Secondary	Length of stay in hospital after surgery.	Length of stay in hospital after surgery.	Up to 30 days after surgery.
Secondary	Rate of all-cause mortality during hospital stay after surgery.	Rate of all-cause mortality during hospital stay after surgery.	Up to 30 days after surgery.
Secondary	Overall survival rate after surgery.	Time from surgery to all-cause death.	Up to 4 year after surgery.
Secondary	Cancer-specific survival after surgery.	Time from surgery to cancer-specific death; deaths from other causes are censored at the time of death.	Up to 4 years after surgery.
Secondary	Activity engagement in 1-year survivors.	Activity engagement is assessed by estimating metabolic equivalents (METs; 1 MET = 3·5 ml/min/kg resting oxygen consumption) for activity in daily life.	At the end of the first year after surgery.