Respons radiasi kanker serviks diduga dapat ditingkatkan dengan pemilihan waktu radiasi tetap yang berpola sirkadian karena dianggap sesuai dengan fase radiosensitif G2-M sel kanker. Daur sirkadian dan melatonin dianggap berperan dalam radiosensitivitas. Dihipotesiskan respons radiasi pagi hari maupun efek samping radiasi pagi hari akan lebih baik dibanding sore hari.
Penelitian ini merupakan uji klinis dengan perolehan subjek secara berurutan. Alokasi pilihan waktu radiasi pada pagi (06.00–08.00) dan sore (16.00–18.00) hari dengan randomisasi blok tiap enam subjek terpisah antara stadium II dan III. Data diperoleh menggunakan metode open label. Pengukuran data klinis seperti ukuran tumor, respons klinis, dan efek samping dilakukan oleh dua dokter independen yang terlatih. Dilakukan pengukuran kadar melatonin dan fase G2-M siklus sel di institusi resmi. Respons baik dan buruk ditetapkan berdasarkan kriteria WHO sedangkan efek samping ada atau tidak, ditetapkan berdasarkan kiriteria RTOG.
Penyinaran di waktu pagi menunjukkan respons klinis lebih baik dibandingkan sore (p 0,025; 95% IK:1,27–33,08; adj OR: 6,48) untuk respons pascaradiasi maupun 2–4 minggu pascaradiasi (p 0,048; 95% IK 1,02–47,81; adj OR 6,98). Kadar Hb awal dan ukuran klinis tumor berpengaruh secara bermakna terhadap respons baik pascaradiasi maupun respons baik 2–4 minggu pascaradiasi. Dalam hal efek samping, pilihan waktu radiasi tidak menunjukkan hasil yang bermakna, namun kadar melatonin praradiasi berpengaruh, khususnya efek samping kulit (p 0,006; 95% IK 1,66–18,99; adj OR 5,62). Variabel yang bermakna memengaruhi efek samping terapi pada gastrointestinal adalah overall treatment time (p 0,031; 95% IK 1,19–39,93; adj OR 6,89), sedangkan untuk genitourinaria adalah PA diferensiasi (p 0,015; 95% IK 1,51–46,37; adj OR 8,36), penurunan berat badan (p 0,025; 95% IK 1,22–18,30; adj OR 4,72), dan nyeri sebelum radiasi (p 0,017; 95% IK 1,31–15,32; adj OR 4,47).
Simpulan: Respons radiasi kanker serviks uteri yang diradiasi pagi hari lebih baik daripada yang diradiasi sore hari, namun efek samping radiasi pagi hari tidak berbeda bermakna dibandingkan sore hari. Belum dapat dipastikan pengaruh besarnya proporsi fase G2-M terhadap respons klinis radiasi. Ada kecenderungan pengaruh kadar melatonin pagi hari terhadap respons klinis radiasi dan terbukti kadar melatonin berpengaruh pada efek samping kulit.
Kata kunci: kanker serviks, melatonin, radiosensitivitas, siklus sel, sirkadian
The radiation response of cervical cancer can be enhanced by the choice of a fixed radiation time of circadian pattern because it is considered to be in accordance with the radiosensitive phase of G2-M cancer cells. Circadian cycles and melatonin are thought to play a role in radiosensitivity. It is hypothesized that the response and side effects of morning radiation will be better than the afternoon.
This study was an RCT (randomized clinical trials) with consecutive sampling. Treatment allocation for radiation time in the morning (06.00–08.00) and afternoon (16.00–18.00) were determined by block randomization for every six subjects based on the stage (II and III). The data was obtained with an open label method. Measurement of clinical data such as tumor size, clinical response, and side effects were carried out by two-trained independent physicians. Measurement of melatonin levels and G2-M phases of cell cycle were carried out in official institution. Good and poor responses were set based on WHO criteria while the side effects were determined based on the RTOG criteria.
Morning radiation showed a better post-radiation and 2–4 weeks post-radiation clinical response compared with afternoon (p 0.025; 95% CI:1.27–33.08; adj OR: 6.48 and p 0.048; 95%CI 1.02–47.81; adj OR 6.98, respectively). The initial Hb level and clinical size of the tumor had a significant effect on good response both post-radiation and 2-4 weeks post-radiation. In regards to the side effects, radiation time did not show significant results in causing side effects, but pre-radiation melatonin level did on skin (p 0.006; 95%CI 1.66–18.99; adj OR 5.62). The significant variable in influencing gastrointestinal side effects was overall treatment time (p 0.031; 95%CI 1.19–3.93; adj OR 6.89), whereas for genitourinaria were differentiation of histopathology (p 0.015; 95%CI 1.51–46.37; adj OR 8.36), weight loss (p 0.025; 95%CI 1.22–18.30; adj OR 4.72), and presence of pain pre-radiation (p 0.017; 95%CI 1.31–15.32; adj OR 4.47).
Conclusion: The radiation response of irradiated uterine cervical cancer is better in the morning than the afternoon. Nevertheless, the side effects of morning radiation do not differ significantly compared to the afternoon. The influence of the G2-M phase proportion on the clinical response to radiation cannot be ascertained. The level of melatonin in the morning might affect the radiation response and affect the side effects on skin.
Keywords: cell cycle, cervical cancer, circadian, melatonin, radiosensitivity.
"Karsinoma sel skuamosa rongga mulut (KSS-RM) merupakan keganasan yang
menempati urutan ke-6 dari seluruh kasus kanker di dunia. Pembedahanmerupakan terapi utama KSS-RM namun pada KSS-RM lanjut lokal,pembedahan merupakan tantangan bagi dokter bedah karena struktur anatomiyang rumit dan dampaknya terhadap kualitas hidup penderita Oleh karena itudipikirkan pemberian kemoterapi neoadjuvan (KN) pada KSS-RM stadium lanjutlokal untuk mengecilkan tumor. Kemoresistensi merupakan masalah pemberianKN pada KSS-RM stadium lanjut lokal akibat microenvironment yang hipoksikditandai dengan peningkatan ekspresi HIF-1α. Kemoresistensi juga diregulasi olehmiR-210 serta peningkatan ekspresi penanda sel punca CD44 dan CD133.Melatonin memiliki efek antioksidan kuat dan efek onkostatik sehinggadiharapkan dapat memperbaiki kondisi hipoksia tumor.Penelitian ini merupakan uji klinis dengan desain paralel acak tersamarpembanding plasebo, yang dilaksanakan pada bulan Juni 2017 hingga Juli 2018,bertujuan untuk mengetahui efektivitas melatonin dalam meningkatkan responsklinis penderita KSS-RM stadium lanjut lokal yang diberikan kemoterapineoadjuvan dan apakah melatonin dapat memperbaiki hipoksia yang ditandaidengan penurunan ekspresi HIF-1α, miR-210, CD44, dan CD133. Sebanyak 50pasien KSS-RM stadium lanjut lokal dari RSCM dan RSKD dirandomisasi.Sebanyak 25 pasien mendapat kombinasi melatonin dan KN (taksan, sisplatin,dan 5-fluorourasil) dan 25 pasien lainnya mendapat KN saja. Sebanyak 25 pasienyang menyelesaikan protokol penelitian (13 pasien kelompok melatonin dan 12pasien kelompok plasebo). Perubahan ekspresi HIF-1α, miR-210, CD44, danCD133 yang diukur dari jaringan biopsi sebelum terapi dan jaringan biopsi/eksisiluas pasca terapi, menggunakan metode qRT-PCR absolute quantification. Selainitu untuk menilai respons klinis digunakan RECIST 1.1 sebelum dan sesudah KN.Melatonin 20 mg perhari menurunkan ekspresi HIF-1α (p = 0,301), miR-210 (p =0,767), dan CD44 (p = 0,103) namun tidak bermakna jika dibandingkan plasebo.Ekspresi CD133 meningkat pada kedua kelompok melatonin dan plasebo (p =0,301) walaupun tidak bermakna. Melatonin 20 mg perhari selama 1 minggusebelum KN pertama dimulai sampai KN selesai tidak memberikan perbedaanrespons positif yang bermakna pada dua kelompok. Penurunan konsentrasi HIF-1a dan CD133 tidak diikuti penurunan persentase sisa tumor. Pada kelompokmelatonin, ekspresi CD44 dan miR-210 menurun diikuti penurunan persentasesisa tumor yang tidak bermakna dibandingkan plasebo. Pada kelompok yangmendapat melatonin, persentase sisa tumor 21,35% lebih rendah dibandingkankelompok plasebo meskipun tidak berbeda bermakna (p = 0,531).Squamous cell carcinoma of the oral cancer (OSCC) is the sixth most common
malignancy of all malignant tumors. Surgery is the mainstay of treatment for oralcavity cancers. Surgery in locally advanced OSCC presents many challengesprimarily because the head and neck region have many critical structures that canbe damaged by tumor or treatment. Damage to these structures can result insignificant structural, cosmetic and functional deficits that negatively impactquality of life. Therefore, it is thought that neoadjuvant chemotherapy (KN) inlocal advanced stage OSCC is to shrink the tumor. The chemoresistancy is aproblem of KN administration in locally advanced OSCC due to a hypoxicmicroenvironment characterized by increased expression of HIF-1α. Thechemoresistancy is also regulated by miR-210 as well as increased expression ofCD44 and CD133 stem cell markers. Melatonin has powerful antioxidant effectsand oncostatic effects that are expected to improve tumor hypoxia.This study is a double-blind, randomized clinical trial, which was carried out inJune 2017 to July 2018 to determine the effectiveness of melatonin in improvingthe clinical response of locally advanced OSCC patients given neoadjuvantchemotherapy and whether melatonin can improve hypoxia marked by decreasedexpression of HIF-1α, miR-210, CD44, and CD133. Only 25 patients hadcompleted the study protocol, 13 in melatonin group and 12 in placebo group. Thedifference in HIF-1α, miR-210, CD44, and CD133 expression were measured as adelta concentration using absolute quantification qRT-PCR. The concentration ofthe biomolecular markers within the tumor tissue taken from the first biopsy (pretreatment)were determined using qRT-PCR then subtracted from theconcentration of biomarkers taken from the second biopsy. The clinical responsewas assessed using RECIST 1.1.The administration of melatonin 20 mg/day decreased the expression of HIF-1α(p = 0,301), miR-210 (p = 0,767), and CD44 (p = 0,103) but not statisticallysignificant. CD133 expression increased in both group melatonin and placebo (p= 0,301). Melatonin 20 mg per day for 1 week before NC was started until NCwas completed did not give a significant difference in positive responses in thetwo groups. The decrease concentrations of HIF-1 and CD133 were not followedby a decrease in the percentage of remaining tumors. The melatonin groupshowed a decrement in CD44 and miR-210 followed by a decrement in thepercentage of remaining tumors that were not significant compared to placebo. Inthis study, melatonin did not increase the clinical response although there is21.35% decrement in tumor mass in melatonin group compare (p = 0,531)."