JOURNAL READING

Influence of perioperative anaesthetic and analgesic interventions

on oncological outcomes: a narrative review

Disusun oleh:

Siti Rodhia Darwin

(1102015228)

Pembimbing:
dr. Rizky Ramadhana, Sp.An

TUGAS KEPANITERAAN KLINIK ST ASE ANESTESI

FAKULTAS KEDOKTERAN UNIVERSITAS YARSI
PERIODE 27 JULI 2020 – 7 AGUSTUS 2020
Ringkasan

Pembedahan adalah perawatan bagi sebagian besar kanker organ solid.

Sering terjadi kekambuhan kanker setelah pembedahanberupa refraktori hingga
kematian pasien. Intervensi perioperatif dapat menginduksi keadaan biologis yang
kondusif untuk kelangsungan hidup dan pertumbuhan sel kanker residual dari
tumor primer intraoperatif dan dapat mempengaruhi risiko metastasis penyakit
berikutnya. Banyak bukti yang menunjukkan bahwa intervensi anestesi dan
analgesik dapat memengaruhi banyak proses patofisiologis tersebut, dapat
menguntungkan atau merugikan. Banyak dari bukti ini berasal dari model
eksperimental in vitro dan in vivo, sebagian besar terbatas pada penelitian
observasional retrospektif dengan bukti klinis atau analisis post hoc dari RCT yang
dirancang untuk mengevaluasi hasil non-kanker.

Ulasan naratif ini merangkum keadaan saat ini bukti mengenai efek
potensial dari intervensi anestesi dan analgesik perioperatif pada biologi kanker dan
hasil klinis. Membuktikan hubungan sebab akibat akan membutuhkan data dari
calon RCT dengan onkologis sebagai titik akhir primer, beberapa di antaranya akan
dilaporkan di tahun-tahun mendatang. Sampai saat itu, tidak ada cukup bukti untuk
merekomendasikan teknik anestesi atau analgesik tertentu untuk pasien yang
menjalani reseksi tumor pembedahan dengan dasar bahwa itu dapat mengubah
risiko kekambuhan atau metastasis.

Keywords: anaesthesia, general; anaesthesia, inhalational; anaesthesia,

intravenous; analgesia; cancer, recurrence; inflammation; opioid; stress response;
surgery

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 Kanker adalah penyebab kematian nomor dua di dunia, mengakibatkan 9,6
juta kematian pada 2018, dan total Insiden global kasus kanker baru diperkirakan
meningkat dari 14 juta pada tahun 2012 menjadi 24 juta pada tahun 2035. Operasi
berpotensi kuratif untuk banyak kanker organ padat, dan lebih dari 80% pasien
dengan kanker akan menjalani setidaknya satu prosedur bedah. Kemudian operasi
terkait kanker membentuk beban kerja yang besar dan meluas untuk ahli bedah dan
ahli anestesi di seluruh dunia.
Rekurensi setelah operasi memberikan morbiditas dan mortalitas yang
tinggi bagi pasien, lebih luas lagi menjadi beban ekonomi. Penyakit metastasis
biasanya refraktori untuk pengobatan, dan sebagian besar kematian akibat kanker
disebabkan oleh metastasis. Rekurensi setelah pembedahan reseksi bervariasi dan
dipengaruhi oleh banyak faktor, seperti organ primer yang terpengaruh, tingkat
tumor dan tahap tumor. Teknik pembedahan mempengaruhi risiko kekambuhan
sebagai persyaratan untuk mencapai margin sampel yang jelas dan meminimalkan
penanganan tumor untuk mencegah penyebaran sel tumor. Pemberian anestesi,
analgesik, atau intervensi perioperatif lainnya (mis. penggunaan steroid, beta
blocker, atau lidokain sistemik) masih belum jelas dapat mempengaruhi
kekambuhan kanker. Studi retrospektif awal menunjukkan bahwa teknik tertentu
mungkin memiliki efek menguntungkan mengurangi tingkat kekambuhan diikuti
oleh orang lain dengan hasil studi yang kontradiktif. Studi laboratorium, meneliti
efek obat anestesi dan analgesik yang umum digunakan pada kanker sel in vitro,
telah menyarankan sinyal bahwa beberapa agen menunjukkan efek antikanker yang
berpotensi menguntungkan dan lainnya berpotensi merugikan kanker. Bukti
definitif membutuhkan uji coba klinik prospektif secara acak. Sampai saat ini,
belum ada uji coba yang diterbitkan yang memeriksa efek dari teknik anestesi atau
analgesik selama primer operasi kanker pada hasil onkologis jangka panjang,
seperti kelangsungan hidup bebas penyakit, meskipun sejumlah penelitian sedang
dalam proses dan baru dilaporkan dalam beberapa tahun mendatang.
Ulasan ini menguraikan kemajuan signifikan yang telah dicapai dibuat
dalam memahami mekanisme patofisiologis pada periode perioperatif yang

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mendasari rekurensi kanker dan metastasis, dan bagaimana agen anestesi dan
analgesic dapat mempengaruhi mereka.

Mekanisme Rekurensi Kanker Pasca Pembedahan

Mekanisme yang mendasari rekurensi kanker pasca bedah rumit dan tidak
sepenuhnya dipahami. Mengikuti sebuah reseksi bedah kuratif yang dimaksudkan
dari tumor primer, kanker dapat kambuh di sejumlah lokasi oleh berbagai
mekanisme:
1. Rekurensi lokal di lokasi reseksi tumor karena proliferasi sel sisa
2. Metastasis kelenjar getah bening karena sel tumor dilepaskan ke sistem
limfatik sebelum atau selama prosedur
3. Metastasis organ jauh karena penyemaian dengan sirkulasi sel tumor (CTC)
dilepaskan sebelum atau selama prosedur
4. Pembibitan dalam rongga tubuh (mis. penyebaran peritoneal)
Kemungkinan sel kanker individu akan 'berkembang biak' menjadi penyakit
metastasis yang signifikan secara klinis dipengaruhi oleh perubahan patofisiologis
yang disebabkan oleh operasi (lihat Gambar 1), dan berpotensi dengan pemberian
anestesi dan pengobatan perioperative termasuk hipotermia dan transfusi darah. Sel
kanker ada di jaringan lingkungan mikro yang melibatkan saling mempengaruhi di
sekitarnya sel stroma non-kanker, sel sistem kekebalan, ekstraseluler matriks,
kemokin, sitokin, dan segudang faktor lainnya. Lingkungan mikro yang halus ini
mudah terganggu trauma jaringan, dan intervensi bedah yang bertujuan untuk
menghilangkan penyakit dapat secara tidak sengaja menciptakan kondisi
menguntungkan tidak hanya kelangsungan hidup, tetapi perkembangan, proliferasi,
dan penyebaran sel kanker residual. Hal yang terjadi seperti keadaan fisiologis yang
diinduksi oleh operasi dan peradangan akan terdapat jaringan hipoksia,
angiogenesis, respons stres bedah, dan imunosupresi. Perubahan ini dapat
mendorong proses dikenal sebagai 'transisi epitel ke mesenkimal', di mana sel-sel
kanker epitel mengembangkan fenotip mesenchymal memfasilitasi motilitas
seluler, dan dengan demikian,memiliki potensi metastasis.

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Respon stres dan imunosupresi
Kekebalan manusia memiliki fungsi penting seperti mengidentifikasi dan
menghilangkan sel-sel kanker. Sel yang dominan dalam 'Pengawasan kekebalan'
adalah sel-sel Natural Killer (NK) dari sistem kekebalan tubuh bawaan dan sel T
CD8 sitotoksik dari sistem kekebalan tubuh adaptif. Setelah operasi, fase awal yaitu
proinflamasi, diikuti oleh periode imunosupresi selama kemampuan sistem
kekebalan untuk mendeteksi dan membasmi sel-sel kanker berkurang. Penekanan
imun ini mungkin terkait dengan kombinasi mekanisme respons stres bedah yang
mengaktifkan Sympathetic Nervous System (SNS) dan Hypothalamice-Pituitarye-
Adrenal (HPA) axis, peningkatan mediator inflamasi pada sirkulas, hipotermia,
darah alogenik transfusi, dan berpotensi pada pemberian anestesi atau analgesik.
Aktivasi HPA axis merangsang pelepasan dari kortisol dan katekolamin, faktor
humoral ini tidak hanya menghambat proliferasi dan aktivitas anti tumor sel NK
dan sel T CD8, tetapi juga mempromosikan proliferasi sel T regulator (Treg) dan
sel T helper 2 tipe (Th2), yang memiliki efek pro-tumor. Sel tumor mengandung ß-
adrenoceptor saat teraktivasi, memicu peningkatan ekspresi faktor terkait dengan
metastasis, termasuk proinflamasi interleukin-6 (IL-6), endotel vaskular pro-
angiogenik faktor pertumbuhan (VEGF), dan enzim matrix metalloprotease

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(termasuk MMP-2 dan MMP-9, yang menurunkan ekstraseluler matriks dan
memfasilitasi mobilitas dan invasi sel kanker)

Inflamasi
Teknik pembedahan yang optimal dapat melukai jaringan normal untuk
mengangkat tumor. Trauma sampai residual bukan jaringan kanker menginduksi
peradangan yang diperlukan untuk respon penyembuhan luka fisiologis dapat
berpotensi merugikan organ-organ lain. Proses inflamasi melibatkan pelepasan
faktor humoral, termasuk prostaglandin (PGE), sitokin (mis. IL-6), faktor nekrosis
tumor alfa, dan kemokin, menghasilkan aktivasi makrofag, neutrofil, dan fibroblast.
Sel-sel yang direkrut melepaskan lebih lanjut sitokin dan faktor pertumbuhan, dapat
mempromosikan penyembuhan jaringan lokal yang diinginkan. Faktor-faktor
namun dapat mendorong viabilitas sel kanker residual di lokasi reseksi dengan
merangsang proliferasi dan migrasi sel kanker, serta menekan kekebalan tubuh
akibat menghambat sitotoksisitas NK. Selain itu, jauh dari lokasi peradangan,
permukaan endotel yang terganggu dan penumpukan faktor pertumbuhan, dapat
memberikan lokasi peradangan yang menguntungkan untuk pembenihan oleh CTC
dibebaskan selama operasi, sebuah fenomena diistilahkan ‘inflamasi oncotaxis'.
Mekanisme yang mendasari peradangan melibatkan peningkatan ekspresi
berbagai komponen inflamasi jalur yang terlibat dalam tumorigenesis
1. Enzim (mis. MMP dan cyclo-oxygenase-2 [COX-2])
2. Faktor transkripsi (mis. faktor yang diinduksi hipoksia 1- alpha [HIF1a],
faktor nuklir kappa-B [NF-kB], dan sinyal transduser dan aktivator
transkripsi 3)
3. (Reseptor kemokin (mis. reseptor kemokin CXC 2 [CXCR2])
Perbedaan ekspresi individu faktor-faktor tertentu antar pasien dapat
memengaruhi perkembangan penyakit (mis. ekspresi berlebih COX-2 dan CXCR2
terlibat dalam perkembangan beberapa jenis kanker). Jalur sel ini telah terjadi
diperiksa sebagai mekanisme potensial untuk menjelaskan bagaimana anestesi dan
analgesik dapat mempengaruhi perkembangan penyakit (mis. lidokain mengurangi
pelepasan MMP dalam sel kanker paru-paru, atau penghambat COX-2)

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Angiogenesis
Perfusi yang terganggu pada jaringan yang terluka menyebabkan hipoksia
lingkungan mikro seluler yang mengarah ke regulasi-atas ekspresi HIF-1a. Faktor
transkripsi ini mempromosikan ekspresi banyak komponen jalur perbaikan
jaringan, termasuk VEGF, matriks ekstraseluler, dan protein adhesi sel.
Angiogenesis yang dihasilkan mendorong penciptaan jaringan sehat baru, tetapi
juga mempromosikan proliferasi residu sel kanker. VEGF juga menyebabkan
pelebaran limfatik dan renovasi di lingkungan tumor, menyediakan kanker sel
dengan rute keluar alternatif dari lokasi peradangan utama. Ekspresi HIF-1a atau
VEGF yang berlebihan dikaitkan dengan buruk prognosis pada banyak jenis
kanker. Modulasi HIF dan ekspresi VEGF oleh obat anestesi dan analgesik,
termasuk agen volatile, anestesi lokal (LA), dan opioid, yang akan dibahas lebih
lanjut dalam artikel ini.

Agen anestesi
Propofol
Propofol adalah i.v. yang paling umum digunakan agen anestesi untuk
induksi dan pemeliharaan anestesi. Studi in vitro telah menunjukkan propofol
memiliki sifat anti-inflamasi serta efek stimulasi pada fungsi kekebalan tubuh,
berpotensi menghasilkan efek menguntungkan pada kekambuhan kanker, meskipun
bukti klinis definitif mengenai hal ini tetap sulit dipahami.
Studi laboratorium
Penelitian praklinis yang berfokus pada imunemodulasi efek propofol.
Tumor dari pasien secara acak diberikan anestesi propofoleparavertebral untuk
operasi kanker payudara terbukti meningkat. Infiltrasi oleh sel T helper, NK dan T
dibandingkan dengan teknik inhalasi. Sugestif dari efek antikanker yang
bermanfaat pada fungsi kekebalan tubuh. Peneliti juga mengambil sampel serum
dari pasien yang menjalani operasi kanker dengan teknik anestesi yang berbeda,
dan meneliti efek serum pada sel imun dan sel kanker in vitro. Dua studi didapatkan
sampel serum pasca bedah dari wanita dengan anestesi secara
propofoleparavertebral untuk operasi kanker payudara memiliki aktivitas sel NK

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donor yang diawetkan secara in vitro, dibandingkan dengan wanita yang menerima
teknik sevofluraneeopioid memiliki aktivitas sel NK lebih rendah pada serum.
Perhatian harus dilakukan ketika menafsirkan hasil studi ini, sebagai individu
kontribusi propofol dan teknik regional untuk hasil yang diukur sulit untuk
dipisahkan dan mekanismenya dari pengamatan tidak dijelaskan. Selanjutnya tidak
semua studi in vitro mendukung hipotesis yang dimiliki propofol efek stimulasi
kekebalan yang bermanfaat: pasien kanker payudara secara acak untuk
propofoleremifentanil atau sevoflurane anestesi ditemukan tidak memiliki
perbedaan pasca operasi konsentrasi sitokin serum atau NK dan Tlymphocyte
sitotoksik.
Selain efek pada fungsi kekebalan tubuh, propofol mungkin mempengaruhi
sel-sel ganas secara langsung melalui berbagai mekanisme diduga. Salah satunya
adalah penghambatan onkogen, seperti gen pengubah sel neuroepitel 1 (NET1) dan
penentuan jenis kelamin wilayah Y kotak 4 (SOX4), yang diekspresikan berlebih
pada kanker tertentu dan terkait dengan prognosis yang lebih buruk. Propofol telah
terbukti mengurangi ekspresi ini pada gen in vitro, yang mengarah ke
penghambatan sel kanker aktivitas. Dalam sel kanker prostat, propofol menghambat
ekspresi reseptor androgen in vitro, menunjukkan potensi efek yang
menguntungkan, seperti stimulasi androgenik terlibat dalam perkembangan kanker
prostat. Selain itu, propofol telah terbukti menurunkan regulasi HIF-1a dalam sel
kanker secara in vitro yang memiliki efek penghambatan potensial pada
angiogenesis, dan berdampak pada pertumbuhan tumor. Bertolak belakang dengan
efek antitumor yang bermanfaat propofol ditemukan dalam banyak penelitian
laboratorium, bahwa propofol mungkin memiliki pro-tumor efek: peningkatan
migrasi sel kanker payudara setelah propofol paparan diamati dalam dua penelitian
Studi klinis
Beberapa studi klinis retrospektif didapatkan risiko kekambuhan kanker
berkuruang pada pasien yang menerima propofol anestesi daripada agen volatile
selama operasi untuk berbagai jenis kanker. Peningkatan kelangsungan hidup
secara keseluruhan berikut teknik berbasis propofol telah ditemukan dalam
penelitian lain. Dalam penelitian retrospektif besar memeriksa jenis anestesi dan

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kelangsungan hidup pasien pasca operasi kanker, 2607 pasien pada kelompok yang
diberikan i.v. dibandingkan dengan kelompok anestesi inhalasi, didapatkan inhalasi
memiliki peningkatan risiko kematian (rasio bahaya [SDM]: 1,46; 95% Interval
kepercayaan [CI]: 1.29-1.66). Ini jelas efek menguntungkan dari propofol belum
ditemukan secara universal: beberapa penelitian retrospektif memeriksa berbagai
operasi kanker melaporkan tidak ada perbedaan dalam kelangsungan hidup atau
kekambuhan antara TIVA dan kelompok berbasis volatile. Secara seimbang, bukti
yang tersedia dari studi retrospektif saat ini tampaknya menyarankan bahwa
propofol mungkin memiliki efek menguntungkan pada menolak metastasis dan
meningkatkan kelangsungan hidup, yang menjamin evaluasi definitif dalam
prospektif, terkontrol secara acak uji klinis. Tidak ada RCT besar yang memeriksa
kekambuhan kanker berikut propofol vs anestesi volatile untuk operasi kanker telah
selesai hingga saat ini. Sedang berlangsung uji coba tercantum pada Tabel 1.

Volatil Anestesi
Agen volatil adalah metode yang digunakan untuk pemeliharaan anestesi
umum di seluruh dunia. Agen anestesi yang mudah menguap memiliki efek pada
sistem kekebalan tubuh dan respons peradangan. Namun, ada bukti yang saling

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bertentangan mengenai apakah volatil diaktifkan atau menghambat jalur ini, dan
masih belum jelas apakah hasil klinis dipengaruhi.
Studi laboratorium
Agen volatil memodulasi respons imun melalui angka target seluler,
termasuk asam gamma-aminobutyric, reseptor glisin, asetilkolin, dan serotonin
serta sel-sel imun, seperti neutrofil, makrofag, dan NK sel. Serum diambil dari
pasien yang menjalani volatil anestesi diamati dibandingkan dengan serum dari
mereka yang menerima teknik propofoleregional terdapat peningkatan aktivitas sel
kanker dan aktivitas NK terhambat. Sebaliknya, sebuah penelitian memeriksa
diferensiasi sel imun dan sitokin pada payudara pasien kanker secara acak baik
propofol atau sevoflurane anestesi tidak menemukan perbedaan yang signifikan
antara keduanya kelompok. Penulis menyimpulkan bahwa ada kekebalan yang
berbeda modulasi terkait dengan agen yang digunakan mungkin minimal.
Agen yang mudah menguap berpotensi memberikan efek langsung pada
kanker sel itu sendiri. Sevoflurane telah terbukti meningkat proliferasi dan migrasi
sel kanker payudara secara in vitro. Volatil juga muncul untuk merangsang migrasi
sel kanker ovarium dan proses pro-metastasis lainnya saat diuji in vitro, dengan
peningkatan ekspresi berbagai faktor pertumbuhan dan penurunan matriks enzim
juga dicatat. Sebaliknya, penelitian lain telah menyarankan bahwa agen inhalasi
dapat langsung menghambat mekanisme seluler yang mendorong metastasis, dan
efek keseluruhan pada kekambuhan mungkin terkait dengan jenis kanker: satu studi
menunjukkan bahwa paparan sevofluran merangsang ginjal kelangsungan hidup
dan migrasi sel kanker, sedangkan sebaliknya, efek penghambatan terlihat dengan
karsinoma paru non-sel kecil (NSCLC) sel.
Volatil Anestesi bersifat melindungi cedera iskemia pada perfusi dalam
berbagai konteks klinis dan sistem organ. Perlindungan ini dikaitkan dengan
ekspresi yang diinduksi dari faktor yang mengatur angiogenesis HIF-1a, suatu
mekanisme yang mungkin melindungi dalam pengaturan cedera reperfusi, tetapi
dalam operasi kanker menignkatkan rekurensi kanker ganas. Isoflurane telah
ditemukan untuk meningkatkan ekspresi HIF dalam sel karsinoma sel prostat dan

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ginjal di Indonesia, kedua temuan terkait dengan peningkatan migrasi dan
proliferasi sel kanker
Studi klinis
Studi klinis retrospektif membandingkan volatile vs propofolbased teknik
sudah dibahas. Singkatnya, Studi-studi ini menunjukkan bahwa agen inhalasi
meningkat risiko kekambuhan kanker dan / atau mengurangi kelangsungan hidup
secara keseluruhan, atau tidak menunjukkan perbedaan di antara keduanya
kelompok dalam hal hasil ini. Sedang berlangsung uji coba tercantum pada Tabel
1.

Anestesi lokal dan anestesi regional

Anestesi lokal memberikan penghambatan sinyal nyeri yang efektif, dengan
blokade neuraxial atau regional baik anestesi intraoperatif dan pasca operasi
analgesia yang efektif. Dalam hal kekambuhan kanker, beberapa manfaat mungkin
bertambah dari teknik regional:
1. Atenuasi dari respons stres dapat mengurangi imunosupresi dan menjaga
kekebalan tubuh bawaan dan kemampuan sistem imun untuk
menghilangkan sisa sel kanker.
2. Mengurangi rasa sakit memungkinkan pengurangan dosis opioid,
melemahkan kemungkinan dampak buruknya kekambuhan pada kanker.
3. Persyaratan volatile anestesi dapat dikurangi untuk mengurangi potensi efek
buruk pada kekambuhan.
4. Bukti yang lebih baru menunjukkan bahwa amide LA berpotensi memiliki
efek antitumor langsung pada sel kanker (lihat di bawah).
Studi laboratorium
Efek anestesi regional pada penanda serum respon stres bedah telah
diperiksa, dengan yang bertentangan hasil. Dalam sebuah penelitian dilakukan
pengacakan terhadap pasien prostatektomi baik analgesia berbasis epidural atau
opioid, kortisol serum dan insulin berkurang pada kelompok pasca prosedur
epidural, tetapi hanya satu sitokin (IL-17) yang meningkat secara signifikan di
kelompok opioid setelah operasi, penulis menyimpulkan analgesia epidural

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melemahkan respons stres, tetapi bukan respons peradangan. Dalam percobaan lain,
kanker kolorektal (CRC) pasien diacak untuk epidural atau pasien terkontrol
analgesia setelah operasi, dan konsentrasi serum sitokin, insulin, dan kortisol diukur
Sekali lagi, perbedaan minimal ditemukan pada peradangan serum sitokin,
menunjukkan bahwa anestesi epidural tidak secara efektif melemahkan respon
inflamasi.
Bukti eksperimental yang masuk akal mendukung hipotesis bahwa amida
LA dapat memberikan efek penghambatan langsung pada tumor sel, berbeda dari
efeknya pada neuron. Bupivacaine in vitro langsung menghambat sel kanker prostat
dan ovarium viabilitas, proliferasi, dan migrasi yang relevan secara klinis. Amide
LAs mengurangi viabilitas sel kanker payudara dan migrasi pada konsentrasi tinggi,
konsentrasi plasma yang tinggi biasanya dihasilkan dari perioperative Infus LA.
Bukti in vivo mendukung efek menguntungkan i.v. lidocaine dalam mengurangi
ukuran tumor dan beban metastasis di model tikus kanker. Tidak jelas seberapa
besar LAide dapat terjadi menggunakan mekanisme kandidat yang memungkinkan
efek antikanker tersebut termasuk efek penghambatan saluran natrium atau
mungkin cara lain, seperti penghambatan onkogen Src atau Demetilasi DNA.
Studi klinis
Terdapat beberapa penelitian yang ingin mengetahui apakah anestesi dapat
mempengaruhi hasil setelah operasi kanker. Beberapa studi klinis retrospektif
selama dekade lalu menyarankan bahwa teknik regional lebih protektif terhadap
kekambuhan kanker. Dalam beberapa tahun terakhir, kebanyakan studi retrospektif
serupa telah diterbitkan (studi terpilih diringkas dalam Tabel 2). Hasilnya
bervariasi, dengan sugestif dari efek menguntungkan anestesi regional pada
kelangsungan hidup secara keseluruhan, kelangsungan hidup bebas rekurensi, atau
kekambuhan biokimia, sementara yang lain telah terdeteksi tidak ada perbedaan
dan minoritas kecil bahkan telah melaporkan merugikan efek.
Heterogenitas penelitian dan banyak temuan yang saling bertentangan, sulit
untuk menggambar kesimpulan keseluruhan teknik regional mempengaruhi
kelangsungan hidup atau kambuh setelah operasi kanker. Sebuah meta-analisis 10
studi yang diterbitkan hingga 2014 memeriksa hasil prostatektomi menemukan

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bahwa teknik regional tidak berhubungan dengan kelangsungan hidup biokimia
yang lebih lama, tetapi dikaitkan dengan peningkatan kelangsungan hidup secara
keseluruhan (HR 0,81; 95% CI: 0.68e0.96; P¼0.016). Meta analisis lain
diidentifikasi 21 Studi (hingga 2014) memeriksa hasil setelah neuraxial anestesi
untuk berbagai operasi kanker, dan mengamati hubungan antara anestesi neuraxial
dan peningkatan kelangsungan hidup keseluruhan (SDM: 0,853; 95% CI:
0,741e0,981; P¼0,026) dan peningkatan kelangsungan hidup bebas rekurensi
(SDM: 0,846; 95% CI: 0.718e0.998; P¼0.047). Namun, meta analisis yang lebih
baru dari 28 studi retrospektif yang diterbitkan hingga 2017 menyimpulkan bahwa
anestesi regional tidak dikaitkan dengan peningkatan bertahan hidup, kelangsungan
hidup bebas kekambuhan, atau bebas biokimia survival. Tinjauan Cochrane terbaru
tentang topik menyimpulkan bahwa bukti untuk kepentingan anestesi regional pada
tumor, kekambuhan tetap tidak adekuat.
Sejumlah uji klinis prospektif acak yang sedang berlangsung sedang bekerja
untuk mengatasi kesenjangan pengetahuan yang cukup besar (lihat Tabel 1). Yang
perlu dicatat, belum ada uji klinis yang signifikan selesai memeriksa efek intravena
perioperative lidokain pada kekambuhan kanker, meskipun ada bukti laboratorium
menyarankan manfaat. NCT02786329 akan memeriksa lidokain dan kambuh
setelah operasi CRC, tetapi dalam jumlah populasi penelitian yang relatif kecil
(n¼450).

Agen analgesik
Opioid
Sebagai agen analgesik yang kuat, opioid banyak digunakan secara
perioperative untuk operasi kanker, dan pengaruhnya terhadap kanker telah
diperiksa di laboratorium dan (sebagian besar retrospektif) klinis studi.
Studi laboratorium
Opioid telah lama dikaitkan dengan efek pada kekebalan tubuh fungsi.
Opioid diketahui bekerja secara tidak langsung pada sistem saraf, menyebabkan
pelepasan amina biologis yang mungkin melemahkan kekebalan bawaan dengan
menghambat sitotoksisitas NK. HPA axis mungkin juga distimulasi, menghasilkan

13
glukokortikoid pelepasan yang secara tidak langsung mengarah ke imunosupresi.
Efek langsung pada fungsi kekebalan tubuh dapat terjadi melalui reseptor opioid,
seperti reseptor mu-opioid (MOR), atau non-opioid reseptor yang diekspresikan
oleh sel imun, termasuk sel NK.
Opioid yang berbeda menghasilkan efek fisiologis yang berbeda pula pada
fungsi kekebalan tubuh. Pada tikus, agonis parsial MOR, buprenorfin, mencegah
depresi sitotoksisitas sel NK dan peningkatan metastasis yang disebabkan oleh
operasi, bertentangan dengan efek yang diamati dari fentanyl dan morfin. Tramadol
mungkin sebenarnya memiliki sifat merangsang kekebalan dan meningkatkan
Sitotoksisitas NK pada tikus. Lebih lanjut, tidak semua laboratorium studi secara
universal mendukung hipotesis bahwa morfin memiliki efek merugikan pada
biologi kanker, dengan sejumlah kecil studi in vitro dan in vivo menemukan itu
morfin memberikan antitumor yang berpotensi memiliki efek yang bermanfaat.
Sel kanker dapat mengekspresikan reseptor opioid secara berbeda jaringan
non-kanker, memungkinkan stimulasi terkait opioid proses tumorigenik, termasuk
migrasi, angiogenesis, dan metastasis. Bukti in vitro menunjukkan bahwa MOR
mengatur pensinyalan reseptor opioid dan diinduksi faktor pertumbuhan,
terkemuka untuk proliferasi dan migrasi sel NSCLC. Pengaruh MOR yang
berbahaya telah terdeteksi secara klinis juga, dengan MOR overexpression yang
terkait dengan klinis retrospektif studi dengan hasil yang lebih buruk pada kanker
prostat dan esophagus kanker sel skuamosa.
Model tikus NSCLC dan kanker payudara telah menunjukkan antagonis
opioid, methylnaltrexone dan naloxone, untuk naik analisis RCT yang dirancang
untuk mengevaluasi efek methylnaltrexone (pada konstipasi pada pasien kanker
yang menerima opioid harian) menemukan peningkatan ketahanan hidup pada
penerima methylnaltrexone, meningkatkan hipotesis bahwa kanker terkait opioid
pertumbuhan dapat dihambat oleh antagonisme MOR.
Meskipun hipotesis beberapa opioid merangsang kanker, harus diingat
bahwa terdapat bukti rasa sakit yang tidak terkontrol dapat mendorong proses
keganasan. Mekanisme ini tidak jelas: mungkin karena peningkatan aktivitas dari
SNS dan HPA axis, dengan peningkatan katekolamin dan glukokortikoid yang

14
beredar merendahkan aktivitas sel-sel imun. Secara klinis, nyeri terkontrol atau
peningkatan kebutuhan opioid memiliki retrospektif telah dikaitkan dengan
kelangsungan hidup yang lebih buruk pada pasien dengan NSCLC. Oleh karena itu,
keseimbangan antara efek imunosupresif dari rasa sakit, di satu sisi, dan opioid, di
sisi lain, mungkin menjadi kunci apakah hasil pengobatan opioid dalam risiko lebih
besar kambuhnya kanker.
Studi klinis retrospektif
Sejumlah penelitian retrospektif telah memeriksa hasil operasi kanker
khusus dalam kaitannya dengan jenis dan kuantitas opioid diberikan secara
perioperatif. Lebih dari 900 pasien yang menjalani operasi untuk NSCLC, pasien
dengan Tahap I penyakit memiliki hubungan yang signifikan antara intraoperatif
tinggi dosis fentanyl dan penurunan kelangsungan hidup secara keseluruhan, dan
menunjukkan tren penurunan kelangsungan hidup bebas rekurensi (HR: 1,12; 95%
CI: 0,99e1.27; P¼0,053); terutama, Tahapan 2 dan 3 pasien tidak memiliki
hubungan yang sama. Pada penelitian lain, walaupun jauh lebih kecil (n¼99), studi
retrospektif NSCLC pasien juga menemukan hubungan antara pemberian opioid
perioperatif dan kambuhnya kanker. Sebaliknya, dalam penelitian lain, tidak ada
hubungan signifikan yang ditemukan antara dosis opioid perioperatif pada pasien
NSCLC dan kelangsungan hidup atau rekurensi keseluruhan. Temuan negatif
serupa dideteksi oleh penelitian retrospektif besar (> 1600 pasien) yang tidak
menemukan hubungan antara fentanil intraoperative dosis dan kelangsungan hidup
bebas rekurensi atau kelangsungan hidup secara keseluruhan di CRC pasien. Hasil
yang bertentangan juga dilaporkan dalam dua studi retrospektif terbaru dari pasien
AS dan Korea yang menjalani pembedahan untuk karsinoma sel skuamosa
esofagus: pengobatan opioid dosis tinggi sangat terkait dengan kekambuhan
penyakit dalam studi Korea, sedangkan AS studi menemukan peningkatan
kelangsungan hidup bebas rekurensi dan secara keseluruhan survival.
Merangkum totalitas bukti tentang pengaruh opioid pada hasil setelah
operasi kanker sulit ditebak mengingat sifat dan hasil studi saat ini sangat beragam.
Sebuah meta-analisis dari 147 publikasi memeriksa pengobatan analgesik pada
model kanker hewan menyimpulkan bahwa, berdasarkan bukti terbatas (opioid

15
diperiksa hanya dalam 32 studi, sebagian besar tidak melibatkan bedah model),
opioid tidak mempengaruhi metastasis. Upaya terbaru pada meta-analisis
kuantitatif perioperative opioid dan kekambuhan CRC mengidentifikasi 13
publikasi menarik, tetapi menganggap mereka terlalu heterogen mengukur efek.
Menurut pendapat penulis, keseimbangan bukti menunjukkan sinyal bahwa opioid
dapat memfasilitasi metastasis dalam kondisi tertentu, tetapi, seperti halnya setiap
intervensi anestesi dibahas dalam ulasan ini, hipotesis harus diuji dalam RCT
prospektif sebelum ada perubahan besar dalam klinis praktik dibenarkan.

Obat antiinflamasi nonsteroid

Pembedahan menyebabkan respons peradangan, yang terlibat pada
kekambuhan kanker, sehingga penghambatan peradangan dapat mengurangi
kekambuhan pasca operasi. Bukti bahwa NSAIDs memiliki efek antikanker yang
bermanfaat, meskipun banyak penelitian telah bersifat epidemiologis dan telah
memeriksa efek NSAID pada hasil kanker di luar konteks bedah
Studi laboratorium
Efek NSAID pada kekambuhan kanker mungkin terkait dengan
pengurangan sintesis prostaglandin karena penghambatan COX atau mungkin
mekanisme lain yang mempengaruhi tumorigenesis, sebagian besar di antaranya
tetap kurang dipahami.Kemungkinan efek terkait NSAID pada faktor-faktor yang
menentukan perkembangan kanker mungkin termasuk efek analgesik hemat opioid,
mengubah ekspresi transkripsi faktor (seperti NF-kB), atau protein pemberi sinyal
(misalnya sebagai reseptor faktor pertumbuhan epidermal). Studi in vitro terdeteksi
efek menguntungkan terkait NSAID, termasuk gangguan viabilitas, proliferasi, dan
migrasi sel kanker, dengan mekanisme yang bergantung pada COX dan independen
COX terlibat. NSAID dan COX-2 inhibitor telah menampilkan berbagai efek
penghambat kanker pada model hewan, terkait dengan mekanisme potensial, seperti
pengurangan VEGF ekspresi dan down-regulasi SOX2 onkogen
Studi klinis
Banyak upaya telah dilakukan untuk mempelajari hasil yang terkait dengan
jangka panjang Pengobatan NSAID (sebelum atau setelah diagnosis) pada pasien

16
kanker. Penggunaan NSAID reguler dikaitkan dengan penurunan CRC kejadian di
observasional dan terkontrol secara acak studi. Penggunaan NSAID secara teratur
juga telah dikaitkan dengan peningkatan kelangsungan hidup bebas rekurensi
setelah operasi di studi observasional memeriksa spektrum kanker yang luas,
termasuk CRC dan kanker payudara. Tidak semua penelitian memiliki
menghasilkan bukti yang jelas tentang manfaat analisis prospektif lebih dari 34.000
pasien kanker payudara tidak terdeteksi adanya hubungan antara penggunaan
NSAID atau COX-2 inhibitor pasca-diagnosis dan kambuhnya kanker payudara,
meskipun digunakan pra-diagnosis tampaknya mengurangi pengulangan.
Selain penggunaan NSAID jangka panjang, perioperative administrasi
NSAID telah diperiksa secara retrospektif studi, dengan hasil variabel terlihat. Satu
kelompok memeriksa pasien kanker payudara mendeteksi hubungan antara
pengobatan perioperative NSAID dan peningkatan hasil kanker. Tidak ada efek
menguntungkan pada hasil kanker dikaitkan dengan administrasi NSAID
perioperatif saja di studi retrospektif memeriksa kanker prostat dan NSCLC operasi.
Namun, kelangsungan hidup yang meningkat telah dilaporkan dengan pengobatan
perioperative NSAID dexamethasone kombinasi dalam studi retrospektif pasien
NSCLC. Prospektif percobaan pengobatan penghambat COX-2 dan hasil kanker
bahkan lebih terbatas lagi untuk memeriksa studi penggunaan rofecoxib pasca
operasi pada pasien CRC dihentikan dini karena kekhawatiran tentang efek
samping kardiovaskular potensial, tanpa perbedaan dalam kelangsungan hidup atau
kekambuhan keseluruhan terdeteksi pada pasien yang direkrut.
Dalam referensi umum, manfaat atau sebaliknya NSAID dalam konteks
operasi kanker telah terbukti sulit. Sebuah ulasan dari 16 studi yang memeriksa
kekambuhan kanker dan penggunaan NSAID perioperatif yang diterbitkan hingga
2017 menemukan studi yang terlalu heterogen atau berkualitas buruk untuk dicoba
meta-analisis, dan penulis menyimpulkan bahwa bukti mendukung efek
menguntungkan dari NSAID perioperatif adalah samar-samar. RCT saat ini sedang
berlangsung, yang diharapkan akan menambah beberapa kejelasan tentang efek
NSAID perioperatif pada kanker hasil, adalah NCT03172988 (Tabel. 1)

17
𝜶-2-Agonis-Adrenoseptor
Meskipun sering digunakan sebagai obat penenang dan analgesik, efek
agonis adrenoseptor a-2 pada kanker jarang terjadi telah dipelajari. Mengingat
umumnya efek pro-tumor katekolamin, dapat dipostulatkan bahwa agen yang sama
mengaktifkan adrenoceptors juga harus menunjukkan mempromosikan efek
kanker. Ini telah ditunjukkan dalam penelitian laboratorium terhadap hewan dan
sel kanker manusia di mana paparan agonis-2 mengakibatkan efek pro-tumoral,
serta efek yang merugikan pada sel sistem kekebalan tubuh bawaan. Sebaliknya,
percobaan kecil secara acal pasien yang menjalani gastrektomi radikal menjadi
dexmedetomidine infus atau saline placebo menemukan bahwa dexmedetomidine
mengakibatkan berkurangnya kadar katekolamin dan sitokin proinflamasi,
memberi kesan yang berpotensi bermanfaat untuk efek antitumor. Sementara
sebagian besar bukti laboratorium menunjukkan efek yang merugikan dari agonis-
2 dalam operasi kanker, harus juga diingat bahwa penggunaan agen tersebut
memungkinkan untuk mengurangi paparan opioid dan volatile anestesi pasien, yang
keduanya dapat berimplikasi pada kekambuhan kanker. Keseimbangan faktor-
faktor ini terletak dalam hal hasil klinis tidak jelas, sampai saat ini, tidak ada
manfaatnya efek pada risiko kekambuhan telah terdeteksi secara klinis (meskipun
retrospektif) memeriksa NSCLC dan kanker payudara pasien.

Intervensi Perioperatif Lainnya

ß-antagonis-adrenoseptor
Meskipun biasanya tidak dianggap sebagai agen analgesik, ß-adrenoceptor
pengobatan antagonis (β-blocker) dapat memperbaiki efek aktivasi SNS yang
diinduksi oleh operasi, karena membatasi efek katekolamin yang mempromosikan
kanker. Penelitian yang meneliti efek ß-blocker pada berbagai kanker tipe sel in
vitro sebagian besar menunjuk bermanfaat pada efek antimetastatik . Manfaat juga
telah terdeteksi di uji klinis, di mana perioperatif ß-blocker digunakan pada pasien
kanker mengurangi sitokin proinflamasi dan mencegah peningkatan pro-tumor
yang diinduksi katekolamin. Meta-analisis awal klinis retrospektif studi yang
meneliti hasil klinis pada pasien kanker disarankan bahwa penggunaan ß-blocker

18
meningkatkan kelangsungan hidup. Meta-analisis yang lebih baru, termasuk 27
studi yang diterbitkan hingga 2018, disimpulkan bahwa ß-blocker tidak memiliki
efek jelas terhadap kambuhnya kanker, dan efek pada kelangsungan hidup bebas
penyakit dan kelangsungan hidup secara keseluruhan bervariasi dengan jenis tumor
mulai dari yang menguntungkan hingga yang berbahaya; penulis mencatat bahwa
basis bukti adalah variabel dan terbatas, terutama dalam hal jenis dan dosis tumor
dan selektivitas ß-blocker yang digunakan.

Deksametason
Kortikosteroid dapat mengurangi efek perangsang kanker respon inflamasi
bedah yang muncul, terutama sebagai terapi perioperatif. Namun, pada dosis yang
lebih tinggi, kortikosteroid juga menyebabkan imunosupresi, berpotensi
meningkatkan risiko kekambuhan. Keseimbangan efek palsu tidak diketahui dan
belum banyak dipelajari untuk hasil operasi pasca kanker. Deksametason umum
digunakan secara intraoperatif sebagai anti-emetik, dan merupakan kandidat yang
ideal untuk diperiksa, namun hasil, hingga saat ini tidak konsisten. Sebuah studi
retrospektif dari 309 pasien menjalani operasi untuk kanker endometrium tidak
menemukan perbedaan dalam risiko kambuh, kelangsungan hidup secara
keseluruhan, atau bebas perkembangan kelangsungan hidup antara mereka yang
menerima deksametason dan mereka yang tidak. Studi kohort retrospektif dari
NSCLC dan pasien kanker pankreas menyarankan perioperative deksametason
dapat dikaitkan dengan peningkatan kelangsungan hidup pasien. Sebaliknya,
mengurangi kelangsungan hidup secara keseluruhan terdeteksi dalam analisis
retrospektif intraoperative deksametason pada pasien kanker dubur. Data prospektif
adalah analisis post hoc terbatas dari studi kecil pasien CRC (n¼60) diacak untuk
deksametason atau plasebo sebelum operasi menemukan bahwa deksametason
meningkatkan risiko metastasis. Sebagian besar sifat retrospektif dan variabel klinis
data tersedia, penelitian berkualitas lebih tinggi diperlukan sebelum penilaian
manfaat atau kortikosteroid bisa dibuat. Satu RCT yang sedang berlangsung adalah
NCT03172988, memeriksa efek deksametason pada hasil pasca operasi NSCLC.

19
Transfusi darah
Transfusi sel darah merah (RBC) dan produk darah lainnya sering
diperlukan selama operasi kanker dan in vitro ini menyebabkan imunosupresi dan
inflamasi diketahui dapat mempengaruhi risiko kekambuhan kanker. Modulasi
imun yang berhubungan dengan transfusi diakui sebagai fenomena patofisiologis
dengan berbagai mekanisme. Makrofag mengonsumsi zat besi yang dilepaskan dari
sel darah merah yang rusak menunjukkan aktivitas fagositik terkompromikan dan
beralih ke respons efektor Th2 pro-tumor, sementara sitokin yang terkandung dalam
produk darah yang ditransfusikan berkontribusi untuk peradangan. Studi in vivo
menunjukkan bahwa pembatalan tersebut efek transfusi meningkat dengan
meningkatnya durasi penyimpanan produk. Bukti klinis dirangkum dalam meta-
analisis retrospektif penelitian menunjukkan efek berbahaya perioperative transfusi
darah alogenik pada hasil (termasuk berulang) dalam berbagai jenis kanker, seperti
kandung kemih, kanker lambung, dan prostat. Sampai saat ini, kualitas terbaik bukti
yang mendukung efek buruk dari transfusi darah pada kanker kambuh telah datang
dari beberapa prospektif studi acak memeriksa pasien CRC 2006 Meta-analisis
Cochrane melaporkan rasio odds keseluruhan untuk kekambuhan 1,42 (95% CI:
1,20e1,67), meskipun studi heterogenitas dan tidak cukup data tentang teknik bedah
dicegah pembentukan definitif dari hubungan sebab akibat. Transfusi darah
dikaitkan dalam praklinis studi dengan peradangan dan imunosupresi. Itu juga
terkait dengan peningkatan risiko kekambuhan kanker pada CRC, tetapi apakah ini
disebabkan oleh pasien kanker sehingga lebih membutuhkan lebih banyak transfusi
atau efek transfusi yang sebenernya peningkatan rekurensi tetap tidak meyakinkan
perkembangan atau pengulangan.

20
21
Kesimpulan
Beberapa bukti dari penelitian laboratorium in vitro dan in vivo serta
sejumlah studi klinis observasional, menyarankan bahwa agen anestesi dan
analgesik tertentu bermanfaat dan lainnya merugikan dalam mencegah kanker.
Studi retrospektif memilikirisiko bias yang signifikan, prospektif RCT dapat benar-
benar menentukan hubungan sebab akibat antara suatu intervensi anestesi dan hasil
kanker. Beberapa RCT seperti saat ini sedang berlangsung, dan hasilnya diharapkan
dalam beberapa tahun ke depan (Tabel 1). Sebagian besar penelitian mempelajari
satu jenis kanker, dan diberikan secara heterogen perilaku biologis dan klinis dari
berbagai kanker, hasil uji coba tidak dapat berlaku untuk semua tipe keganasan.
Oleh karena itu, di masa depan dapat dipelajari efek anestesi dan analgesia pada
hasil untuk jenis kanker yang tidak dibahas dalam penelitian ini.
Ketika mempertimbangkan prioritas untuk penelitian masa depan dapat
diperhatikan bahwa lidokain sistemik sebagian besar tetap tidak dipelajari dalam

22
hasil klinis meskipun terdapat bukti laboratorium yang signifikan menunjukkan
manfaat pada efek anti-metastatik amida LA. Teknik yang paling menjanjikan
didukung oleh data secara ilmiah untuk uji klinis di masa depan adalah propofol
TIVA vs sevoflurane anestesi inhalasi, dengan dan tanpa lidokain sistemik
perioperative infus. Evaluasi teknik dengan daya penelitian desain faktorial yang
memadai, membutuhkan sekitar 6000 pasien dan masa tindak lanjut yang cukup
besar. Sementara itu, di tidak adanya bukti klinis kerusakan yang terkait dengan
agen, dan sementara kami menunggu data percobaan acak berkualitas baik untuk
mendukung manfaat terkait agen, masih ada kekurangan data untuk mengubah
praktik klinis saat ini.

Kontribusi penulis
Structure/outline/overall direction: DJB.
Literature review: TW.
Current evidence synthesis: TW.
Writing first draft: TW.
Critical revision: AS, DM, DJB.
All authors read and approved the final manuscript.

Declaration of interest
DJB and DM are board members of the British Journal of Anaesthesia.

23
 British Journal of Anaesthesia, 123 (2): 135e150 (2019)

doi: 10.1016/j.bja.2019.04.062
Advance Access Publication Date: 27 June 2019
Review Article

CLINICAL PRACTICE

Influence of perioperative anaesthetic and analgesic interventions

on oncological outcomes: a narrative review
T. Wall1,2,*, A. Sherwin1,2, D. Ma2,3 and D. J. Buggy1,2,4
1
Department of Anaesthesiology and Perioperative Medicine, Mater University Hospital, School of Medicine, University
College Dublin, Dublin, Ireland, 2EU-COST Action 15204, Euro-Periscope, Avenue Louise 149, 1050 Brussels,
Belgium, 3Department of Anaesthesia, Imperial College School of Medicine, London, UK and 4Outcomes Research,
Cleveland Clinic, Cleveland, OH, USA

*Corresponding author. E-mail: tom.p.wall@gmail.com

Summary
Surgery is an important treatment modality for the majority of solid organ cancers. Unfortunately, cancer recurrence
following surgery of curative intent is common, and typically results in refractory disease and patient death. Surgery and
other perioperative interventions induce a biological state conducive to the survival and growth of residual cancer cells
released from the primary tumour intraoperatively, which may influence the risk of a subsequent metastatic disease.
Evidence is accumulating that anaesthetic and analgesic interventions could affect many of these pathophysiological
processes, influencing risk of cancer recurrence in either a beneficial or detrimental way. Much of this evidence is from
experimental in vitro and in vivo models, with clinical evidence largely limited to retrospective observational studies or
post hoc analysis of RCTs originally designed to evaluate non-cancer outcomes. This narrative review summarises the
current state of evidence regarding the potential effect of perioperative anaesthetic and analgesic interventions on
cancer biology and clinical outcomes. Proving a causal link will require data from prospective RCTs with oncological
outcomes as primary endpoints, a number of which will report in the coming years. Until then, there is insufficient
evidence to recommend any particular anaesthetic or analgesic technique for patients undergoing tumour resection
surgery on the basis that it might alter the risk of recurrence or metastasis.

Keywords: anaesthesia, general; anaesthesia, inhalational; anaesthesia, intravenous; analgesia; cancer, recurrence;
inflammation; opioid; stress response; surgery

Cancer is the second leading cause of death worldwide,
resulting in 9.6 million deaths in 2018, and the overall global
incidence of new cancer cases is predicted to increase from 14
million in 2012 to 24 million by 2035.1,2 Surgery is potentially
curative for many solid organ cancers, and over 80% of pa-
tients with cancer will undergo at least one surgical proced-
ure.3 Unsurprisingly then, cancer-related surgeries form a
large and expanding workload for surgeons and anaesthetists
worldwide.
Recurrence following surgery presents a huge morbidity
and mortality burden for patients, as well as a wider societal
and economic burden. A metastatic disease is typically re-
fractory to treatment, and the majority of cancer-related
deaths are due to metastasis.4 Recurrence following surgical
resection varies dramatically and is influenced by many fac-
tors, including primary organ affected and tumour grade and
stage. Undoubtedly, surgical technique affects recurrence risk
given the requirement to achieve clear sample margins and
minimise tumour handling to prevent the dispersal of tumour
cells. What is less clear is whether anaesthetic, analgesic, or
other perioperative interventions (e.g. the use of steroids, beta
blockers, or systemic lidocaine) may also have an influence on
cancer recurrence.5 Initial retrospective studies suggesting
that certain techniques may have beneficial effects on
reducing recurrence rates were followed by others with con-
tradictory results. Laboratory studies, examining the effects of

Editorial decision: 23 April 2019; Accepted: 23 April 2019

© 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
For Permissions, please email: permissions@elsevier.com

135
 136 - Wall et al.
commonly used anaesthetic and analgesic drugs on cancer
cells in vitro, have suggested a signal that some agents
demonstrate potentially beneficial anticancer effects and
others potentially detrimental cancer-promoting effects.6
Definitive evidence requires prospective, randomised clinical
trials. To date, no trial has been published that examines the
effect of an anaesthetic or analgesic technique during primary
cancer surgery on long-term oncological outcomes, such as
disease-free survival, although a number are in progress and
should report in the coming years.
This review outlines the significant progress that has been
made in understanding the pathophysiological mechanisms
in the perioperative period that underlie cancer recurrence
and metastasis, and how anaesthetic and analgesic agents
may influence them.
Mechanisms of cancer recurrence following
surgery
The mechanisms underlying post-surgical cancer recurrence
are complex and incompletely understood. Following an
intended curative surgical resection of a primary tumour,
cancer may recur at a number of sites by a variety of
mechanisms:7
(i) Local recurrence at the tumour resection site due to pro-
liferation of residual cells
(ii) Lymph-node metastasis due to tumour cells released into
the lymphatic system before or during the procedure
(iii) Distant organ metastasis due to seeding by circulating
tumour cells (CTCs) released before or during the
procedure
(iv) Seeding within a body cavity (e.g. peritoneal spread)
Fig. 1. Schematic representation of the pathophysiological mechanisms induced by surgery that promote survival and growth of meta-
static deposits formed by circulating tumour cells (CTCs) released intraoperatively. COX-2, cyclo-oxygenase-2; HIF, hypoxia-inducible
factor; HPA, hypothalamicepituitaryeadrenal axis; IL-6, interleukin 6; MMP, matrix metalloprotease; NF-kB, nuclear factor kappa B; NK,
natural killer cell; Th2, Type 2 helper T cell; Treg, regulatory T cell; VEGF, vascular endothelial growth factor. Created with BioRender.
The likelihood that individual cancer cells will ‘seed’ in
tissue and progress to a clinically significant metastatic dis-
ease is influenced by pathophysiological changes induced by
surgery (see Fig. 1), and potentially by anaesthesia and peri-
operative events, including hypothermia and blood trans-
fusion.8 Cancer cells exist in a complex tissue
microenvironment involving the interplay of surrounding
non-cancerous stromal cells, immune system cells, extracel-
lular matrix, chemokines, cytokines, and myriad other fac-
tors.9 This delicate microenvironment is easily disrupted by
tissue trauma, and the surgical intervention aiming to elimi-
nate the disease may inadvertently create conditions that
promote not only survival, but progression, proliferation, and
spread of residual cancer cells. Such surgery-induced physio-
logical changes are numerous and include inflammation, tis-
sue hypoxia, angiogenesis, surgical stress response, and
immunosuppression.7 These changes can drive the process
known as ‘epithelial-to-mesenchymal transition’, whereby
epithelial cancer cells develop a mesenchymal phenotype
facilitating cellular motility, and thus, metastatic potential.10
Stress response and immunosuppression
Identifying and eliminating cancer cells are a crucial function
of human immunity, and prominent in the delivery of this
‘immune surveillance’ are the natural killer (NK) cells of the
innate immune system and the cytotoxic CD8þ T cells of the
adaptive immune system.11 After surgery, there is an initial
pro-inflammatory phase, followed by a period of immuno-
suppression during which the immune system’s ability to
detect and eradicate cancer cells is diminished.12 This sup-
pression may be related to a combination of mechanisms,
including the surgical stress response activating the
 Anaesthesia and outcome following cancer surgery
sympathetic nervous system (SNS) and the hypothal-
amicepituitaryeadrenal (HPA) axis, increased circulating in-
flammatory mediators, hypothermia, allogeneic blood
transfusion, and potentially anaesthetic or analgesic
agents.7,13,14 Activation of the HPA axis stimulates the release
of cortisol and catecholaminesdthese humoral factors not
only inhibit the proliferation and antitumour activity of NK
cells and CD8þ T cells, but also promote the proliferation of
regulatory T cells (Tregs) and Type 2 helper T cells (Th2), which
have pro-tumour effects.7 Tumour cells bear ß-adrenoceptors
that, upon activation, trigger the increased expression of fac-
tors associated with metastasis, including pro-inflammatory
interleukin-6 (IL-6), pro-angiogenic vascular endothelial
growth factor (VEGF), and matrix metalloprotease enzymes
(including MMP-2 and MMP-9, which degrade extracellular
matrix and facilitate cancer cell mobility and invasion).8
Inflammation
Even an optimal surgical technique necessarily injures normal
tissue in order to remove a tumour. Trauma to residual non-
cancerous tissue induces inflammation required for the
physiological wound-healing response to occur, but is poten-
tially detrimental to other organs.15 The inflammatory process
involves the release of humoral factors, including prosta-
glandins (PGE), cytokines (e.g. IL-6), tumour necrosis factor
alpha, and chemokines, resulting in the recruitment and
activation of macrophages, neutrophils, and fibroblasts.16
Recruited cells release further cytokines and growth factors,
which promote desirable localised tissue healing. Unfortu-
nately, these factors may also promote residual cancer cell
viability at the site of resection by stimulating cancer cell
proliferation and migration, as well as depressing the immune
function by inhibiting NK cytotoxicity.17,18 Moreover, distant
sites of inflammation, with disrupted endothelial surfaces and
bathed in growth factors, may provide favourable sites for
seeding by CTCs liberated during surgery, a phenomenon
termed ‘inflammatory oncotaxis’.19
The mechanisms underlying inflammation involve the
increased expression of numerous components of inflamma-
tory pathways implicated in tumorigenesis, including20
(i) Enzymes (e.g. MMP and cyclo-oxygenase-2 [COX-2])
(ii) Transcription factors (e.g. hypoxia-inducible factor 1-
alpha [HIF-1a], nuclear factor kappa-B [NF-kB], and signal
transducer and activator of transcription 3)
(iii) Chemokine receptors (e.g. CXC chemokine receptor 2
[CXCR2])
Individual differences of expression of certain factors be-
tween patients may influence disease progression (e.g. over-
expression of COX-2 and CXCR2 is implicated in progression of
several cancer types).21,22 These cellular pathways have been
examined as potential mechanisms to explain how anaes-
thetic and analgesic agents may influence disease progression
(e.g. lidocaine reducing MMP release in lung cancer cells, or
COX-2 inhibitors inhibiting angiogenesis).23,24
Angiogenesis
The disrupted perfusion of injured tissue produces a hypoxic
cellular microenvironment leading to the up-regulated
expression of HIF-1a. This transcription factor promotes the
expression of many components of tissue repair pathways,
including VEGF, extracellular matrix, and cell adhesion
- 137
proteins.25 The resultant angiogenesis drives the creation of
new healthy tissue, but also promotes the proliferation of re-
sidual cancer cells.26 VEGF also causes lymphatic dilation and
remodelling in the tumour environment, providing cancer
cells with alternative exit routes from the primary site.27
Overexpression of HIF-1a or VEGF is associated with poor
prognosis in numerous cancer types.28,29 Modulation of HIF
and VEGF expression by anaesthetic and analgesic drugs,
including volatile agents, local anaesthetics (LA), and opioids,
has been postulated and is discussed further in this
article.30e32
Anaesthetic agents
Propofol
Propofol is the most commonly used i.v. anaesthetic agent for
induction and maintenance of anaesthesia. In vitro studies
have shown propofol to possess anti-inflammatory properties
as well as stimulatory effects on immune function, potentially
resulting in beneficial effects on cancer recurrence, although
definitive clinical evidence of this remains elusive.33
Laboratory studies
Considerable preclinical research has focused on the immune-
modulating effects of propofol. Tumours excised from pa-
tients randomised to receive propofoleparavertebral anaes-
thesia for breast cancer surgery were shown to have increased
infiltration by NK and T helper cells compared with an inha-
lational technique, suggestive of a beneficial anticancer effect
on immune function.34 Researchers also sampled serum from
patients undergoing cancer surgery under different anaes-
thetic techniques, and examined the effect of this serum on
immune cells and cancer cells in vitro. Two studies found that
serum sampled after operation from women randomised to
propofoleparavertebral anaesthesia for breast cancer surgery
preserved donor NK cell activity in vitro, compared to reduced
NK activity with serum from women receiving a
sevofluraneeopioid technique.35,36 Caution must be exercised
when interpreting the results of these studies, as the individ-
ual contributions of propofol and regional techniques to
measured outcomes are difficult to separate and the mecha-
nisms of the observations are not elucidated. Furthermore, not
all in vitro studies support the hypothesis that propofol has
beneficial immune-stimulating effects: breast cancer patients
randomised to either propofoleremifentanil or sevoflurane
anaesthesia were found to have no difference in postoperative
serum cytokine concentrations or NK and cytotoxic T-
lymphocyte numbers.37
Aside from any effect on immune function, propofol
possibly affects malignant cells directly through a variety of
putative mechanisms. One is inhibition of oncogenes, such as
neuroepithelial cell-transforming gene 1 (NET1) and sex-
determining region Y box 4 (SOX4), which are overexpressed
in certain cancers and associated with poorer prognosis.38
Propofol has been shown to reduce the expression of these
genes in vitro, leading to the inhibition of cancer cell
activity.39e41 In prostate cancer cells, propofol inhibits
androgen receptor expression in vitro, indicating a potential
beneficial effect, as androgenic stimulation is implicated in
prostate cancer progression.42 Additionally, propofol has been
shown to down-regulate HIF-1a in cancer cells in vitrodwith
potential inhibitory effects on angiogenesis, and therefore,
 138 - Wall et al.
tumour growth.43 Contrary to the beneficial antitumour effects
of propofol found in much laboratory research, isolated
studies have suggested that propofol may possess pro-tumour
effects: increased breast cancer cell migration following pro-
pofol exposure was observed in two studies.44,45
Clinical studies
Several retrospective clinical studies have detected reduced
cancer recurrence risk in patients who received propofol-based
anaesthesia rather than volatile agents during surgery for
various cancer types.46,47 Improved overall survival following
propofol-based techniques has been found in other studies.48,49
In a large retrospective study examining anaesthesia type and
patient survival post-cancer surgery, 2607 patients in the i.v.
group were propensity matched with an equal number in the
inhalational groupdinhalational anaesthesia was associated
with an increased risk of death (hazard ratio [HR]: 1.46; 95%
confidence interval [CI]: 1.29e1.66) following a multivariable
analysis of confounders in the matched group.50 These apparent
beneficial effects of propofol have not universally been found:
several retrospective studies examining a variety of cancer sur-
geries reported no difference in either survival or recurrence
between TIVA and volatile-based groups.51e53 On balance,
however, available evidence from retrospective studies currently
appears to suggest that propofol may have beneficial effects in
resisting metastasis and improving survival, which warrants a
definitive evaluation in a prospective, randomised controlled
clinical trial. No large RCT examining cancer recurrence
following propofol vs volatile anaesthesia for cancer surgery has
been completed to date. A number of such trials are underway
and are listed in Table 1.
Volatile anaesthesia
Volatile agents are the most commonly used method for the
maintenance of general anaesthesia worldwide. It is estab-
lished that volatile anaesthetic agents have effects on the
immune system and the inflammatory response.54,55 Howev-
er, conflicting evidence exists as to whether volatiles activate
or inhibit these pathways, and it remains unclear whether
clinical outcomes are influenced.
Laboratory studies
Volatile agents modulate the immune response via a number
of cellular targets, including gamma-aminobutyric acid,
glycine, acetylcholine, and serotonin receptors present on
immune cells, such as neutrophils, macrophages, and NK
cells.56 Serum taken from patients who underwent volatile
anaesthesia was observed to stimulate cancer cell activity and
inhibit NK activity compared to serum from those receiving a
propofoleregional technique.35,36,57 In contrast, a study
examining immune cell and cytokine differentiation in breast
cancer patients randomised to either propofol or sevoflurane
anaesthesia found no significant differences between the two
groups, with the authors concluding that any differential im-
mune modulation related to the agents used may be
minimal.58
Volatile agents potentially exert direct effects on cancer
cells themselves. Sevoflurane has been shown to increase
breast cancer cell proliferation and migration in vitro.59 Vola-
tiles also appear to stimulate ovarian cancer cell migration and
other pro-metastatic processes when tested in vitro, with
increased expression of a variety of growth factors and matrix-
degrading enzymes also noted.60,61 Conversely, other studies
have suggested that inhalational agents may actually directly
inhibit cellular mechanisms that drive metastasis, and that
any overall effect on recurrence may be related to cancer type:
one study showed that sevoflurane exposure stimulated renal
cancer cell viability and migration, whereas an opposite,
inhibitory effect was seen with non-small-cell lung carcinoma
(NSCLC) cells.62
Volatile anaesthetics are known to be protective against
ischaemiaereperfusion injury in a variety of clinical contexts
and organ systems.63 This protection is associated with
induced expression of the angiogenesis-regulating factor HIF-
1a, a mechanism that is perhaps protective in the setting of
reperfusion injury, but in cancer surgery promotes malignant
recurrence.64 Isoflurane has been found to increase the
expression of HIF in prostate and renal cell carcinoma cells in
separate studies, both findings associated with increased
cancer cell migration and proliferation.43,65
Clinical studies
Retrospective clinical studies comparing volatile vs propofol-
based techniques have already been discussed. In summary,
these studies have either shown that inhalational agents in-
crease the risk of cancer recurrence and/or decrease the
overall survival, or have shown no difference between the two
groups in terms of these outcomes.46e48,50,51,53 Ongoing pro-
spective trials are listed in Table 1.
Local anaesthetics and regional anaesthesia
Local anaesthetics provide effective inhibition of pain signal
transmission, with neuraxial or regional blockade providing
both effective intraoperative anaesthesia and postoperative
analgesia. In terms of cancer recurrence, several benefits may
accrue from regional techniques:
(i) Attenuation of the stress response may reduce the asso-
ciated immunosuppression and preserve the innate im-
mune system’s ability to eliminate residual cancer cells.
(ii) Reduced pain allows for opioid dose reduction, attenu-
ating their possible detrimental effect on cancer
recurrence.
(iii) Volatile anaesthetic requirements may be reduced, also
reducing any potential adverse effect on recurrence.
(iv) More recent evidence suggests that amide LAs potentially
possess direct antitumour effects on cancer cells (see
below).
Laboratory studies
The effect of regional anaesthesia on serum markers of the
surgical stress response has been examined, with conflicting
results. In a study randomising prostatectomy patients to
either epidural or opioid-based analgesia, serum cortisol and
insulin were reduced in the epidural group post-procedure,
but only one cytokine (IL-17) was significantly elevated in the
opioid group after operation, with the authors concluding that
epidural analgesia attenuates the stress response, but not the
inflammatory response.66 In another trial, colorectal cancer
(CRC) patients were randomised to epidural or patient-
controlled analgesia after operation, and serum concentra-
tions of cytokines, insulin, and cortisol were measured.67
 Anaesthesia and outcome following cancer surgery - 139

Table 1 Selected ongoing prospective RCTs listed on clinicaltrials.gov and updated in 2018e9, which examine anaesthetic techniques
and post-surgical cancer outcomes. GA, general anaesthesia; RA, regional anaesthesia.

Study ID Title Design Intervention Cancer outcome Estimated

measurements completion

NCT00418457 Regional Anesthesia and Multicentre prospective Volatileþopioids vs 1 : Cancer March 2019
Breast Cancer RCT (n¼1311) propofol TIVAþRA recurrence rate
Recurrence
NCT03034096 General Anesthetics in Multicentre prospective Propofol TIVA vs 1 : Overall survival December
Cancer Resection RCT (n¼2000) volatile 2 : Recurrence- 2020
Surgery free survival
NCT02786329 Influence of Anesthesia on Single-centre prospective 22: Propofol vs 1 : Overall survival December
Postoperative Outcome 22 factorial RCT (n¼450) volatile; lidocaine and recurrence 2021
and Complications in vs placebo rate
Colorectal Cancer
Patients
NCT03109990 Impact of Multicentre prospective Intraoperative 1 : Overall survival April 2024
Dexmedetomidine on RCT (n¼460) dexmedetomidine and recurrence
Postoperative Tumor infusion vs placebo rate
Recurrence in Patients
with Breast Cancer
NCT03172988 Dexamethasone, Multicentre prospective 22: Flurbiprofen, 1 : Overall survival August 2023
Flurbiprofen Axetil and 22 factorial RCT (n¼844) dexamethasone, at 3 yr
Long-Term Survival saline, and lipid 2 : Recurrence-
After Lung Cancer microspheres free survival
Surgery
NCT02840227 Effect of Combined GA/RA Multicentre prospective GAþepidural vs 1 : Cancer-free December
on Cancer Recurrence in RCT (n¼2000) GAþopioids survival 2021
Patients Having Lung
Cancer Resections

Again, a minimal difference was found in serum inflammatory
cytokines, suggesting that epidural anaesthesia does not
effectively attenuate the inflammatory response.
Plausible experimental evidence supports the hypothesis
that amide LAs may exert direct inhibitory effects on tumour
cells, distinct from their effects on neurones. In vitro, bupiva-
caine directly inhibits prostate and ovarian cancer cell
viability, proliferation, and migration at clinically relevant
concentrations.68 Amide LAs reduce breast cancer cell viability
and migration at high concentration, however, not at low
plasma concentrations typically resulting from perioperative
LA infusions.69 In vivo evidence supports a beneficial effect of
i.v. lidocaine in reducing tumour size and metastatic burden in
mouse models of cancer.70e72 It is unclear how amide LAs may
exert such an anticancer effectdpossible candidate mecha-
nisms include their known sodium channel inhibitory effect or
possibly other means, such as inhibition of the Src oncogene or
DNA demethylation.73e75
Clinical studies
Much of the current interest in whether anaesthesia may in-
fluence outcomes following cancer surgery was spurred by the
publication of several retrospective clinical studies over a
decade ago, which suggested that regional techniques may be
protective against cancer recurrence.76,77 In recent years, a
plethora of similar retrospective studies have been published
(selected studies are summarised in Table 2). Results have
been varied, with some suggestive of a beneficial effect of
regional anaesthesia on overall survival, recurrence-free sur-
vival, or biochemical recurrence, whilst others have detected
no difference and a small minority has even reported detri-
mental effects.
Given the heterogeneity of the studies involved and their
widely conflicting findings, it is difficult to draw an overall
conclusion as to whether regional techniques affect survival
or recurrence following cancer surgery. A meta-analysis of 10
studies published up to 2014 examining outcomes following
prostatectomy found that regional techniques were not asso-
ciated with longer biochemical recurrence-free survival, but
were associated with improved overall survival (HR 0.81; 95%
CI: 0.68e0.96; P¼0.016).112 Another meta-analysis identified 21
studies (up to 2014) examining outcomes following neuraxial
anaesthesia for a range of cancer surgeries,113 and observed an
association between neuraxial anaesthesia and improved
overall survival (HR: 0.853; 95% CI: 0.741e0.981; P¼0.026) and
improved recurrence-free survival (HR: 0.846; 95% CI:
0.718e0.998; P¼0.047). However, a more recent meta-analysis
of 28 retrospective studies published up to 2017 concluded
that regional anaesthesia was not associated with improved
survival, recurrence-free survival, or biochemical recurrence-
free survival.114 The most recent Cochrane review of the
topic concluded that evidence for a benefit of regional anaes-
thesia on tumour recurrence remains inadequate.115
A number of ongoing prospective randomised clinical trials
are working to address the considerable knowledge gap (see
Table 1). Of note, no significant clinical trial has yet been
completed examining the effect of perioperative intravenous
lidocaine on cancer recurrence, despite laboratory evidence
suggesting benefit. NCT02786329 will examine lidocaine and
recurrence following CRC surgery, but in a relatively small
study population (n¼450).
 140 - Wall et al.

Table 2 Selected retrospective studies of regional anaesthesia and clinical outcomes. BCR, biochemical recurrence; CSS, cancer-
specific survival; GA, general anaesthesia; HR, hazard ratio; OR, odds ratio; OS, overall survival; PCA, patient-controlled analgesia;
PFS, progression-free survival; PVB, paravertebral block; RCT-PHA, RCT-post hoc analysis; RFS, recurrence-free survival; TURBT, trans-
urethral resection of bladder tumour; PCEA, patient-controlled epidural analgesia.

Study authors Year Type Surgery type Techniques compared Significant results

Biki and colleagues76 2008 RC Radical prostatectomy GAþepidural (n¼102); 57% reduction in BCR in
GAþopioid (n¼123) epidural group
78
Tsui and colleagues 2010 RCT-PHA Radical prostatectomy GAþepidural (n¼49); GA No difference in disease-
(n¼50) free survival
Wuethrich and colleagues79 2010 RC Radical prostatectomy GAþepidural (n¼105); Improved PFS in epidural
GAþopioid/NSAID group (HR: 0.45); no
(n¼158) difference in BCR, CSS, or
OS
Forget and colleagues80 2011 RC Radical prostatectomy GAþepidural (n¼578); No difference in BCR-free
GA (n¼533) survival
81
Wuethrich and colleagues 2013 RC Radical prostatectomy GAþepidural (n¼67); No difference in BCR, RFS,
GAþopioid/NSAID or OS
(n¼81)
Roiss and colleagues82 2014 RC Radical prostatectomy GAþspinal (n¼3047); No difference in BCR, RFS,
GA alone (n¼1725) or OS
Sprung and colleagues83 2014 RC Radical prostatectomy GAþepidural (n¼486); No difference in RFS, CSS,
GAþopioids (n¼486) or OS
Scavonetto and colleagues84 2014 RC Radical prostatectomy GAþneuraxial GA alone associated with
(n¼1642); GA alone increased systemic
(n¼1642) progression (HR: 2.81;
P¼0.008) and mortality
(HR: 1.32; P¼0.047)
Tseng and colleagues85 2014 RC Radical prostatectomy Spinalþsedation No difference in BCR
(n¼1166); GA (n¼798)
Lee and colleagues86 2017 RC Thoracotomy for lung GAþepidural (n¼619); PVB associated with
cancer GAþPVB (n¼536); increased OS; no
GAþPCA (n¼574) difference with epidural
or PCA; no difference in
recurrence between the
three groups
Christopherson and colleagues87 2008 RCT-PHA Colectomy GAþepidural (n¼85); GA Improved OS with epidural
(n¼92) in those without
metastases at time of
surgery, but only up to
1.46 yr postoperative
Gottschalk and colleagues88 2010 RC Colectomy GAþepidural (n¼256); No difference in RFS
GA (n¼253) overall; improved RFS in
patients aged >64 yr
Gupta and colleagues89 2011 RC Colectomy GAþepidural (n¼562); Epidural use for rectal (HR:
GAþPCA (n¼93) 0.45) cancers associated
with improved OS; no
difference seen for colon
cancers
Cummings and colleagues90 2012 RC Colectomy GAþepidural (n¼9670); Improved OS in epidural
GA (n¼32 481) group (HR: 0.91), but no
difference in cancer
recurrence
Day and colleagues91 2012 RC Laparoscopic GAþepidural (n¼107); No difference in OS or 5 yr
colectomy GAþspinal (n¼144); disease-free survival
GAþPCA (n¼173)
Holler and colleagues92 2013 RC Colectomy GAþepidural (n¼442); Improved OS in epidural
GA (n¼307) group (HR: 0.73)
Vogelaar and colleagues93 2015 RC Colectomy GAþepidural (n¼399); Improved OS in GA group
GA (n¼189) (HR: 0.77)
Hiller and colleagues94 2014 RC Gastrectomy or GAþepidural (n¼97); GA Epidurals associated with
oesophagectomy (n¼43) improved OS and RFS at
2 yr in oesophagectomy
group; no difference in
gastrectomy group
Cummings and colleagues95 2014 RC Gastrectomy GAþepidural (n¼766); No difference in OS or
GA (n¼1979) recurrence rate
Heinrich and colleagues96 2015 RC Oesophagectomy GAþepidural (n¼118); No difference in RFS or OS
GA (n¼35)
Li and colleagues97 2016 RC Oesophagectomy GAþepidural (n¼178); No difference in OS or
GA (n¼178) recurrence risk

Continued
 Anaesthesia and outcome following cancer surgery - 141

Table 2 Continued

Study authors Year Type Surgery type Techniques compared Significant results

Shin and colleagues98 2017 RC Gastrectomy Epidural PCA (n¼4325); No difference in OS or RFS
i.v. PCA (n¼374)
99
Wang and colleagues 2017 RC Gastrectomy GAþepidural (n¼1390); Improved OS in epidural
GA (n¼2856) group (HR: 0.65)
Lacassie and colleagues100 2013 RC Advanced ovarian GAþepidural (n¼37); GA No difference in OS or time
cancer (n¼43) to recurrence
Lin and colleagues101 2011 RC Ovarian serous GAþepidural (n¼106); Decreased OS in
adenocarcinoma GAþopioids (n¼37) GAþopioids group (HR:
1.214)
de Oliveira and colleagues102 2011 RC Ovarian cancer GAþepidural (n¼55); GA Intraoperative epidural use
debulking (n¼127) associated with reduced
recurrence risk (HR: 0.37)
Capmas and colleagues103 2012 RC Ovarian cancer GAþPCEA (n¼47); GA No difference in OS or RFS
complete (n¼47)
cytoreduction
Tseng and colleagues104 2018 RC Ovarian cancer GAþepidural (n¼435); Improved PFS and OS in
debulking GA (n¼213) epidural group
Doiron and colleagues105 2016 RC Radical cystectomy GAþepidural (n¼887); No difference in OS or CSS
GA (n¼741)
106
Weingarten and colleagues 2016 RC Radical cystectomy GAþspinal (n¼195); GA No difference in OS or RFS
(n¼195)
Chipollini and colleagues107 2018 RC Radical cystectomy GAþepidural (n¼215); Worse RFS (HR: 1.67) and
GA (n¼215) CSS (HR: 1.53) in epidural
group
Choi and colleagues108 2017 RC TURBT Spinal (n¼718); GA Lower recurrence rate in
(n¼158) spinal group (HR: 0.636)
Koumpan and colleagues109 2018 RC TURBT Spinal (n¼135); GA Increased recurrence rate
(n¼96) (OR: 2.06) and earlier
time to recurrence (HR:
1.57) in GA group
Zimmitti and colleagues110 2016 RC Colorectal liver GAþepidural (n¼390); Epidural associated with
metastectomy GA (n¼120) improved RFS (HR: 0.74),
but not OS
Exadaktylos and colleagues77 2006 RC Breast GAþPVB (n¼50); Increased recurrence-free
GAþopioid (n¼79) survival in PVB group at 3
yr (88% vs 77%; P¼0.012)
Myles and colleagues111 2011 RCT-PHA Abdominal cancer GAþepidural (n¼230); No difference in OS or RFS
surgery GA (n¼216)

Analgesic agents metastasis enhancement caused by surgery, contrary to the

Opioids
As potent analgesic agents, opioids are widely used perioper-
atively for cancer surgery, and their effects on cancer have
been examined in laboratory and (largely retrospective) clin-
ical studies.
Laboratory studies
Opioids have long been associated with effects on immune
function. Opioids are known to act indirectly on the nervous
system, causing the release of biological amines that may
attenuate innate immunity by inhibiting NK cytotoxicity.116
The HPA axis might also be stimulated, resulting in glucocor-
ticoid release leading indirectly to immunosuppression.117
Direct effects on immune function may occur via opioid re-
ceptors, such as the mu-opioid receptor (MOR), or non-opioid
receptors expressed by immune cells, including NK cells.116,118
Different opioids produce different physiological effects on
immune function. In rats, the MOR partial agonist, buprenor-
phine, prevented the depression of NK cell cytotoxicity and
observed effects of fentanyl and morphine.117 Tramadol may
actually possess immune-stimulating properties and en-
hances NK cytotoxicity in rats.119 Furthermore, not all labo-
ratory studies are universally supportive of the hypothesis
that morphine has detrimental effects on cancer biology, with
a small number of both in vitro and in vivo studies finding that
morphine exerts potentially beneficial antitumour
effects.32,120,121
Cancer cells can express opioid receptors differently to
non-cancerous tissue, enabling opioid-related stimulation of
tumorigenic processes, including migration, angiogenesis, and
metastasis.122 In vitro evidence suggests that MOR regulates
opioid and growth-factor-induced receptor signalling, leading
to the proliferation and migration of NSCLC cells.123,124 The
harmful influence of MOR has been detected clinically as well,
with MOR overexpression associated in retrospective clinical
studies with poorer outcomes in prostate cancer and oeso-
phageal squamous cell cancer.125,126
Mouse models of NSCLC and breast cancer have shown the
opioid antagonists, methylnaltrexone and naloxone, to
 142 - Wall et al.
possess cancer-inhibiting effects.127,128 Additionally, a follow-
up analysis of RCTs designed to evaluate the effect of meth-
ylnaltrexone (on constipation in cancer patients receiving
daily opioids) found improved survival in methylnaltrexone
recipients, raising the hypothesis that opioid-related cancer
growth may be inhibited by MOR antagonism.129
Despite the hypothesised cancer-stimulating effects of
some opioids, it must be borne in mind that evidence exists
that poorly controlled pain may drive malignant processes.130
The mechanism is unclear: it may be due to increased activity
of both the SNS and the HPA axis, with the subsequent in-
crease in circulating catecholamines and glucocorticoids
attenuating the activity of immune cells.131 Clinically, poorly
controlled pain or increased opioid requirements have retro-
spectively been associated with poorer survival in patients
with advanced NSCLC.132 Therefore, the balance between the
immunosuppressive effects of pain, on one hand, and opioids,
on the other, may be the key to whether opioid treatment re-
sults in greater risk of cancer recurrence.
Retrospective clinical studies
Numerous retrospective studies have examined cancer sur-
gery outcomes specifically in relation to the type and quan-
tity of opioid administered perioperatively. In over 900
patients undergoing surgery for NSCLC, patients with Stage 1
disease had a significant association between high intra-
operative fentanyl dose and decreased overall survival, and
showed a trend towards reduced recurrence-free survival
(HR: 1.12; 95% CI: 0.99e1.27; P¼0.053); notably, Stages 2 and 3
patients did not share similar associations.133 A similar,
albeit much smaller (n¼99), retrospective study of NSCLC
patients also found an association between opioid adminis-
tration perioperatively and cancer recurrence.134 Conversely,
in another study, no significant association was found be-
tween perioperative opioid dose in NSCLC patients and
overall survival or recurrence.135 Similar negative findings
were detected by a large (>1600 patients) retrospective study
that found no association between intraoperative fentanyl
dose and recurrence-free survival or overall survival in CRC
patients.136 Conflicting results were also reported in two
recent retrospective studies of US and Korean patients un-
dergoing surgery for oesophageal squamous cell carcinoma:
high-dose opioid treatment was strongly associated with
disease recurrence in the Korean study, whereas the US
study found improved recurrence-free survival and overall
survival.137,138
Summarising the totality of evidence regarding the influ-
ence of opioids on outcomes following cancer surgery is
predictably difficult given the widely varying nature and re-
sults of studies to date. A meta-analysis of 147 publications
examining analgesic treatment in animal cancer models
concluded that, on the basis of limited evidence (opioids
were examined in only 32 studies, most not involving sur-
gical models), opioids do not influence metastasis.139 The
most recent attempt at quantitative meta-analysis of peri-
operative opioids and CRC recurrence identified 13 publica-
tions of interest, but deemed them too heterogeneous to
quantify an effect.140 In our opinion, the balance of evidence
suggests a signal that opioids may facilitate metastasis in
certain conditions, but, as with every anaesthetic interven-
tion discussed in this review, the hypothesis must be tested
in a prospective RCT before any major change in clinical
practice is justified.
Non-steroidal anti-inflammatory drugs
Surgery causes an inflammatory response, which is implicated
in cancer recurrence, so it follows that inhibition of inflam-
mation may reduce postoperative recurrence.141 Evidence is
growing that NSAIDs have beneficial anticancer effects,
although many studies have been epidemiological in nature
and have examined NSAID effects on cancer outcomes outside
a surgical context.142
Laboratory studies
NSAID effects on cancer recurrence may be related to reduced
prostaglandin synthesis due to COX inhibition or possibly
other mechanisms affecting tumorigenesis, most of which
remain poorly understood.143 Possible NSAID-related effects
on factors determining cancer progression may include
opioid-sparing analgesic effects, altered expression of tran-
scription factors (such as NF-kB), or signalling proteins (such
as epidermal growth factor receptor).144 In vitro studies have
detected beneficial NSAID-related effects, including impaired
cancer cell viability, proliferation, and migration, with both
COX-dependent and COX-independent mechanisms impli-
cated.145,146 NSAIDs and COX-2 inhibitors have displayed a
range of cancer-inhibiting effects in animal models, associ-
ated with potential mechanisms, such as reduced VEGF
expression and down-regulation of the SOX2
oncogene.27,147,148
Clinical studies
Much effort has been spent studying outcomes related to long-
term NSAID treatment (prior to or after diagnosis) in cancer
patients. Regular NSAID use is associated with reduced CRC
incidence in observational and randomised controlled
studies.149 Regular NSAID use has also been associated with
improved recurrence-free survival following surgery in
observational studies examining a broad spectrum of cancers,
including CRC and breast cancer.150,151 Not all studies have
produced clear evidence of benefitda prospective analysis of
over 34 000 breast cancer patients detected no association
between post-diagnosis NSAID or COX-2 inhibitor use and
breast cancer recurrence, although pre-diagnosis use
appeared to reduce recurrence.152
Aside from long-term NSAID use, the perioperative
administration of NSAIDs has been examined in retrospective
studies, with variable results seen. One group examining
breast cancer patients detected an association between peri-
operative NSAID treatment and improved cancer out-
comes.153,154 No beneficial effects on cancer outcomes were
attributed to perioperative NSAID administration alone in
retrospective studies examining prostate cancer and NSCLC
surgery.80,155,156 However, enhanced survival has been re-
ported with perioperative combined NSAIDedexamethasone
treatment in retrospective studies of NSCLC patients.157 Pro-
spective trials of COX-2 inhibitor treatment and cancer out-
comes have been even more limiteddone study examining
postoperative rofecoxib use in CRC patients was terminated
early due to concerns over potential cardiovascular side-
effects, with no difference in overall survival or recurrence
detected in recruited patients.158
In a common refrain, summarising the benefits or other-
wise of NSAIDs in a cancer surgery context has proven diffi-
cult. A review of 16 studies examining cancer recurrence and
 Anaesthesia and outcome following cancer surgery
perioperative NSAID use published up to 2017 found the
studies either too heterogeneous or poor quality to attempt a
meta-analysis, and the authors concluded that evidence sup-
porting a beneficial effect of perioperative NSAIDs is equiv-
ocal.159 An RCT currently underway, which hopefully will add
some clarity to the effect of perioperative NSAIDs on cancer
outcomes, is NCT03172988 (see Table 1).
a-2-Adrenoceptor agonists
Despite their frequent use as sedative and analgesic agents,
the effects of a-2-adrenoceptor agonists on cancer have rarely
been studied. Given the generally pro-tumour effects of cate-
cholamines, it may be postulated that agents that similarly
activate adrenoceptors should also exhibit cancer-promoting
effects. This has been shown in laboratory studies of animal
and human cancer cells where exposure to a-2 agonists
resulted in pro-tumoral effects, as well as detrimental effects
on innate immune system cells.160e163 Conversely, a small trial
randomising patients undergoing radical gastrectomy to dex-
medetomidine infusion or saline placebo found that dexme-
detomidine resulted in reduced levels of catecholamines and
pro-inflammatory cytokines, suggesting a potentially benefi-
cial antitumour effect.164 Whilst most laboratory evidence
points to a detrimental effect of a-2 agonists in cancer surgery,
it must also remembered that the use of such agents may
allow for reduced patient exposure to opioids and volatile
anaesthetics, both of which may be implicated in cancer
recurrence. Where the balance of these factors lies in terms of
clinical outcomes is unclear, however, to date, no beneficial
effects on recurrence risk have been detected in clinical (albeit
retrospective) studies examining NSCLC and breast cancer
patients.153,165
Other perioperative interventions
b-adrenoceptor antagonists
Although not typically regarded as analgesic agents per se, ß-
adrenoceptor antagonist (ß-blocker) treatment may ameliorate
the effects of surgery-induced SNS activation, and thus, limit
the resulting cancer-promoting effects of catecholamines.
Indeed, studies examining ß-blocker effects on various cancer
cell types in vitro have largely pointed to beneficial anti-
metastatic effects.166,167 Benefits have also been detected in
clinical trials, in which perioperative ß-blocker use in cancer
patients reduced pro-inflammatory cytokines and prevented
the catecholamine-induced elevation of pro-tumour
Tregs.168,169 Initial meta-analyses of retrospective clinical
studies examining clinical outcomes in cancer patients sug-
gested that ß-blocker use improves survival.170,171 However, a
more recent meta-analysis, including 27 studies published up
to 2018, concluded that ß-blockers have no evident effect on
cancer recurrence, and effects on disease-free survival and
overall survival vary with tumour type from beneficial to
harmful; the authors do note that the evidence base is variable
and limited, especially in terms of tumour type and dosage
and selectivity of ß-blocker used.172
Dexamethasone
Corticosteroids may reduce the cancer-stimulating effects of
the surgical inflammatory response and appear, notionally at
least, to hold promise as a perioperative therapy. However, at
higher doses, corticosteroids also induce immunosuppression,
- 143
potentially increasing the recurrence risk.173 Where the bal-
ance of effects lies is unknown and has not been widely
studied for outcomes post-cancer surgery. Dexamethasone is
commonly used intraoperatively as an anti-emetic, and thus,
is an ideal candidate to examine; however, results, to date,
have been inconsistent. A retrospective study of 309 patients
undergoing surgery for endometrial cancer found no differ-
ence in recurrence risk, overall survival, or progression-free
survival between those that received dexamethasone and
those that did not.174 Recent retrospective cohort studies of
NSCLC and pancreatic cancer patients suggested that periop-
erative dexamethasone may be associated with improved
patient survival.157,175 Conversely, reduced overall survival
was detected in a retrospective analysis of intraoperative
dexamethasone in rectal cancer patients.176 Prospective data
are limitedda post hoc analysis of a small study of CRC patients
(n¼60) randomised to dexamethasone or placebo pre-surgery
found that dexamethasone increased the metastasis risk.177
Given the largely retrospective and variable nature of clinical
data available, higher-quality studies are required before a
judgement on the benefits or otherwise of corticosteroids can
be made. One RCT underway is NCT03172988, examining the
dexamethasone effect on outcomes post-NSCLC surgery.
Blood transfusion
Transfusion of red blood cells (RBCs) and other blood products
is frequently required during cancer surgery and in vitro this
causes immunosuppression and inflammationdfactors
known to adversely affect cancer recurrence risk.178
Transfusion-related immune modulation is recognised as a
pathophysiological phenomenon with various mechanisms
suspected.14 Macrophages consuming iron released from
damaged RBCs demonstrate compromised phagocytic activity
and shift towards pro-tumour Th2 effector responses, while
cytokines contained in transfused blood products contribute
to inflammation.179 In vivo studies suggest that the cancer-
stimulating effects of transfusion increase with increasing
product storage duration.180
Clinical evidence summarised in meta-analyses of retro-
spective studies has suggested a harmful effect of periopera-
tive allogeneic blood transfusion on outcomes (including
recurrence) in a variety of cancer types, such as bladder,
gastric, and prostate cancer.181e183 To date, the best-quality
evidence supporting a detrimental effect of blood trans-
fusion on cancer recurrence has come from several prospec-
tive randomised studies examining CRC patientsda 2006
Cochrane meta-analysis reported an overall odds ratio for
recurrence of 1.42 (95% CI: 1.20e1.67), although study hetero-
geneity and insufficient data on surgical technique prevented
the definitive establishment of a causal relationship.184 In
summary, blood transfusion is associated in preclinical
studies with inflammation and immunosuppression. It is also
associated with increased risk of cancer recurrence in CRC, but
whether this is attributable to patients with more aggressive
cancer needing more transfusion or a true effect of transfusion
increasing recurrence remains inconclusive.
Conclusions
Some evidence from in vitro and in vivo laboratory studies, as
well as a number of observational clinical studies, suggests a
signal that certain anaesthetic and analgesic agents are
beneficial, and others detrimental, in preventing cancer
 144 - Wall et al.
progression or recurrence. Retrospective studies are inher-
ently limited by their significant risk of bias, and only a pro-
spective RCT can truly determine a causal link between an
anaesthetic intervention and altered cancer outcomes. Several
such RCTs are currently ongoing, and the results are expected
within the next few years (Table 1). However, these trials
largely study one cancer type, and given the widely hetero-
geneous biological and clinical behaviour of different cancers,
trial results may not be reliably applicable to all malignancies.
Therefore, considerable work will remain in the future to
establish the effects of anaesthesia and analgesia on outcomes
for cancer types not addressed in these studies.
When considering priorities for future research, it must be
noted that systemic lidocaine remains largely unstudied in
terms of clinical outcomes despite significant laboratory evi-
dence of benefit pointing to an anti-metastatic effect of amide
LAs. Perhaps then, the most promising techniques supported
by the most scientifically plausible data for a future clinical
trial are propofol TIVA vs sevoflurane inhalational anaes-
thesia, with and without a perioperative systemic lidocaine
infusion. Evaluating these techniques in an adequately pow-
ered 22 factorial design trial, with oncological primary and
secondary endpoints,185 would require approximately 6000
patients and a considerable period of follow-up. Meanwhile, in
the absence of clinical evidence of harm associated with any
agent, and whilst we await good-quality randomised trial data
to support agent-related benefit, there still remain insufficient
data to change the current clinical practice.186
Authors’ contributions
Structure/outline/overall direction: DJB.
Literature review: TW.
Current evidence synthesis: TW.
Writing first draft: TW.
Critical revision: AS, DM, DJB.
All authors read and approved the final manuscript.
Declaration of interest
DJB and DM are board members of the British Journal of
Anaesthesia.
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