Perioperative epidural analgesia for major abdominal surgery and recurrence-free survival: randomised trial

Perioperative epidural analgesia for major abdominal surgery and recurrence-free survival: randomised trialPaul S Myles, Philip Peyton, Brendan Silbert, Jennifer Hunt,John R A Rigg, Daniel I SesslerJURNAL READING1Oleh: Halim Sudono

Pembimbing: Prof. Dr. dr. Nancy Margarita Rehatta, SpAn. KIC. KNA.

Departemen / SMF Anestesiologi dan ReanimasiFakultas Kedokteran Universitas Airlangga / RSU dr. Soetomo Surabaya 2015

IntroductionSurgeryrelease cancer cells into the circulationdepresses cell mediated immunityreduces circulating concentrations of tumor related antiangiogenic factorsincreases concentrations of pro-angiogenic factorsreleases growth factors that promote local and distant growth of malignant tissue

Complete surgical eradication of cancer:AnesthesiaImpairs many immune functionOpioidsInhibit cellular and humoral immune function in humanspro-angiogenic and promotes growth of breasttumours in rodentsIntroductionRegional anesthesia and analgesia:prevents the neuroendocrine stress response to surgery by blocking afferent neural transmission from reaching the CNS and by blocking descending efferent activation of the sympathetic nervous system volatile anesthetics and sparing postoperative opioids release of endogenous opioids opioid induced immune impairmentIn animals reduce the metastatic burden in animals inoculated with breast adenocarcinoma cellsIn humans two reported beneficial effects in breast cancer and prostate cancerthree reported no beneficial effects in colon cancer, prostate cancer, and cervical cancerone equivocal results in prostate cancer METHODSThis is an follow up study of MASTER trialMASTER was a multicentre randomised clinical trial designed to test the hypothesis that combined epidural and general anesthesia reduces the frequency of a composite end point of mortality and major postoperative complications compared with general anasthesia and opioid analgesia

Study design and participantsDesign : Long term follow-up of prospective randomised controlled clinical trial in which patients were randomly assigned to receive general anesthesia with or without epidural block for at least three postoperative daysParticipants : 503 adult patients who had potentiallycurative surgery for cancer (complete surgical excision of cancer) esophagectomy, gastrectomy, hepatectomy, pancreatectomy, colectomy, nephrectomy, cystectomy, radical hysterectomy,and open prostatectomySetting : 23 hospitals in Australia, New Zealand, and AsiaMETHODSStudy Profile

METHODSFollow up data : the patients medical record from the source hospital, hospital surgery or pathology databases (or both), the patient s general practitioner, state based cancer registry or national death index (or both), letter of introduction followed by telephone contact of the patient, and letter of introduction followed by telephone contact of the patient s next of kin

METHODSCause of death : cancer, cardiovascular disease, sepsis, and other causes

Study end points:primary end point of the study : cancer-free survival after surgerythe secondary endpoint : survival (all cause mortality)

Statistical analysis:Intention to treat principleKaplan Meier survival estimates and log-rank testOutcomes of cancer (five year survival and five year disease-free survival) 2 test and multivariate logistic modelSPSS for Windows, version 18 for analysesMETHODSRESULT

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DISCUSSIONHost defense is well established as the primary determinant of progression of cancer, and function of NK cells is the single most important component. The stress response to surgery, volatile anesthesia, and opioid administration all directly impair natural killer cell function, and each effect is ameliorated by spinal/epidural anesthesia. In vitro, animal, and some observational human data suggestedthat epidural block would substantially reduce the risk of recurrence of cancer, but this study fail to support this hypothesis: recurrence-free survival and mortality were nearly identical in both groups and any subgroup included in the analysis.This study identified other factors that were associated with poorer cancer-free survival after surgery : older age, female sex, tumor-nodes metastases status (results not shown), and intraoperative red cell transfusion. These exploratory findings are consistent with many previous studies.

DISCUSSIONOther studies: Benefit:Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Biki B, Mascha E, Moriarty DC, Fitzpatrick JM, Sessler DI, Buggy DJ Anesthetic technique for radical prostatectomy surgery affectscancer recurrence: a retrospective analysis.No benefit:Gottschalk A, et al. Association between epidural analgesia and cancer recurrence after colorectal cancer surgery. Tsui BC, Rashiq et al. Epidural anesthesia and cancer recurrence rates after radical prostatectomy. 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 studybut this studies were small and not randomized thus affected by selection bias and confoundingDISCUSSIONStrength:compared its 9-15 years outcomes in a relatively large group of patients who were randomly assigned to general anesthesia combined with epidural anesthesia and analgesia versus general anesthesia and opioid analgesiawell powered to detect a one third treatment effect but lacked power to reliably detect smaller effects that might still be of considerable clinical importance, particularly for individual types of cancer

LimitationThis study does not provide information on the effects of regional blockade on non-abdominal (for example, breast) cancers.

CONCLUSIONEven though this study could not identify any reduction in recurrence of cancer or survival when epidural block was used for surgery for abdominal cancer, it doesnt meant that Regional analgesia (especially epidural block) is an inferior choice because it still provide a good post operative pain treatment, can limit opioid related side effects and reduce the risk of hypotension. CRITICAL APPRAISALCLINICAL QUESTIONCan regional anesthesia reduce the risk of recurrence in patient undergoing cancer surgery compared to general anesthesia?

PICOPICOClinical QuestionJournalPPatient undergoing cancer surgery503 adult patients who had potentiallycurative surgery for cancerIRegional anesthesiageneral anaesthesia with epidural block for at least three postoperative daysCGAGAOrisk of recurrencelong term recurrence of cancer andsurvival of patients Design, Journal Focus & WorksheetDesign : prospektif cohortFokus Jurnal : prognosisWorksheet : prognosisTelaah Kritis Jurnal : ValidityRAMMBOTelaah ValiditasJawaban Sesuai WorksheetRecruitmentApakah sampel yang mewakili pasien dimasukkan dalam penelitian pada waktuperjalanan penyakitnyasama?Ya.Penelitian ini adalah follow up dari MASTER trialRAMMBOTelaah ValiditasJawaban Sesuai WorksheetAllocationBagaimana pasien diperlakukan? Jika ada subkelompok dengan prognosis berbeda, apakah dilakukan penyesuaian untuk faktor prognosis yang penting?Ya.

Telaah Kritis Jurnal : ValidityRAMMBOTelaah ValiditasJawaban Sesuai WorksheetMaintenanceApakah status kelompok dipertahankan tetap sebanding dengan manajemen yang sama? dan follow up yang memadai?Ya

Telaah Kritis Jurnal : ValidityRAMMBOTelaah ValiditasJawaban Sesuai WorksheetMeasurementBlindingOutcomeApakah subjek dan penilai "disamarkan" terhadap perlakuan yang diterima dan/atau pengukurannya objektif?Ya. Telaah Kritis Jurnal : ValiditityTelaah ImportancyJawaban Sesuai WorksheetApakah kemaknaan statistik &kemaknaan klinis dari hasil penelitiantergambar dengan baik?YaPengukuran apa yang digunakandan seberapa dampak perlakuannya?Cancer free survival (hazard ratio)Mungkinkah dampak terjadikarena kebetulan?

Tidak. Telaah Kritis Jurnal : ImportancyTelaah Kritis Jurnal : ApplicabilityTelaah ApplicabilityJawaban Apakah PICO jurnal yang diperolehsesuai PICO pertanyaan klinis?Ya.Apakah pasien anda cukup mirip denganpasien dalam penelitian?Ya.Apakah intervensi dalam penelitian ini dapat diterapkan untuk manajemen pasien di lingkungan anda?Ya. Akankah potensi manfaat lebih besardibanding potensi merugikan bila intervensi ini diaplikasikan pada pasien anda?Ya. Apakah hasil penelitian ini dapatdiintegrasikan dengan nilai-nilai sertaharapan pasien anda?Ya.