Evre 2-3 kolon kanserinde adjuvan kemoterapi kararında etkili prognostik faktörler ve mikrosatellit instabilitenin önemi
Effective prognostic factors and importance of microsatellite instability in the decision of adjuvant chemotherapy in stage 2-3 colon cancer
Yazar: ÖZGÜR ÖZBEY
Danışman: PROF. DR. MEHMET KÜÇÜKÖNER
Dicle Üniversitesi / Tıp Fakültesi / İç Hastalıkları Ana Bilim Dalı / Onkoloji Bilim Dalı
Derece: Tıpta Uzmanlık, 2020
Konu: Onkoloji = Oncology ; İç Hastalıkları = Internal diseases
Dizin: Kanser =   ; Kolon hastalıkları = Colonic diseases ; Kolon neoplazmları = Colonic neoplasms ; Kolorektal neoplazmlar = Colorectal neoplasms ; Mikrosatelitler = Microsatellites ; Neoplazm evreleri = Neoplasm staging ; Neoplazmlar = Neoplasms ; Prognoz = Prognosis ; İlaç tedavisi = Drug therapy

Özet:
Amaç: Kolorektal kanserler dünya genelinde en sık görülen 3. malignitedir. Adjuvan
kemoterapi evre 3 hastalara standart tedavi olarak kullanılmasına rağmen evre 2
hastaların hepsine verilmemektedir. Evre 2 kolorektal kanserde yüksek risk faktörleri
olan hastalara adjuvan kemoterapi verilmektedir. Kolorektal kanserde en önemli
prognostik faktör hastalığın evresidir. Evre II de yüksek risk belirteçleri T4 evre
olması; yüksek grade kötü diferansiye histoloji (taşlı yüzük hücreli, musinoz tümör),
lenfovasküler invazyon (LVI), perinöral invazyon (PNİ), barsak obstrüksiyonu
ve/veya perforasyonu kapalı (perforasyon da dahil), cerrahi sınır pozitifliği, cerrahi
spesmenlerde 12 ve altında lenf nodu disseke edilmiş olması, yüksek preoperatif
CEA düzeyi (>5) gibi durumlardır. Bunlara ek olarak mikrosatellite durumu adjuvan
kemoterapi değerlendirilmesi için kullanılan önemli bir prognostik değer olarak
kabul edilmektedir. Bizde çalışmamızda kolorektal kanserli hastalarda mikrosatellite
instabilite dahil bu risk faktörlerinin prognostik önemini ve sağkalım ilişkilerini
analiz ettik.
Yöntem: Bu çalışmaya 2001-2020 yılları arasında Dicle Üniversitesi Tıp Fakültesi
Hastanesi Onkoloji Bölümü'ne başvuran 388 erken evre (evre 2-3) kolorektal kanser
tanılı hasta ve MS durum verileri incelenen 58 hasta (metastatik ve metastatik
olmayan) retrospektif olarak dahil edildi. Hastaların verilerine HBYS(Hastane Bilgi
Yönetim Sistemi) üzerinden ulaşıldı. Hastaların yaş, cinsiyet, evre, patolojik olarak
T evre, N evre, grade, lenfovasküler-perinöral invazyon bilgileri, tümör
lokalizasyonu, adjuvan kemoterapi alıp almaması ve MSS/MSI(Mikrosatellit
stabil/Mikrosatellit instabil) durumlarına göre hastalıksız sağkalım ve genel sağkalım
durumları analiz edildi.
Bulgular: Çalışmaya dahil edilen 388 hastanın 199'u (%51,3) erkek, 189'u (%48,7)
ise kadın cinsiyetde, 246'sı (%59) evre 2 olup 142 'si (%42) evre 3'dü. Hastaların
ortanca yaşı 53 (19-94) olarak tespit edildi. Tümör lokalizasyonu açısından 314
(%81,3) hasta sol kolon yerleşimli iken 72 (%18,7) hasta sağ kolon yerleşimliydi.
Bunlardan 186'sı (%48,2) rektum, 128'i (%33,2) sigmoid kolon, 46'sı (%11,9) çıkan
kolon, 26'sı (%6,7) transvers kolon yerleşimliydi. Tüm grupta hastaların medyan
hastalıksız sağkalım süresi 91,7 ay (64,3-119,2). Evre 2 hastaların medyan 
hastalıksız sağkalım süresi 135,7 ay (107-164,5), evre 3 hastaların medyan
hastalıksız sağkalım süresi 47 ay (27,8-67,3) saptandı . Evre 2 hastalarda medyan
hastalıksız sağkalım süresi istatiksel olarak daha uzun bulundu (p< 0,001).
Hastaların 281'i (%78,4) adjuvan kemoterapi alırken 77'si (%21,5) hastaya adjuvan
kemoterapi verilmemiş ve geri kalan hastaların ise tedavi bilgisine ulaşılamamıştı.
Evre 2 hastaların 166'ı (%72,8) adjuvan kemoterapi alırken 62'si (%27,2)
kemoterapi almamıştı, evre 3 hastaların ise 122'si (%87,7) adjuvan kemoterapi
tedavisi alırken 17 (%12,3) hasta adjuvan kemoterapi almamış. Evre 2 ve evre 3
hastalarda adjuvan kemoterapi tedavi alanlarda hastalıksız sağkalım 111 ay iken
almayanlarda 79 ay olarak klinik anlamlılığa sahip ancak istatistik anlamlılık
yoktu(p=0,5). Risk faktörlerinden olan lenfovasküler-perinöral invazyon (LVİ-PNİ)
durumuna göre hastaların ortalama hastalıksız sağkalım süresi 54,6 ay (30,3-78,9)
iken LVİ-PNİ olmayan hastaların ortalama hastalıksız sağkalım süresi 94,1 ay (74,4-
113,8) saptandı ve istatiksel olarak anlamlı idi (p=0,015). Mikrosatellit(MS) durumu
ve hastalıksız sağkalım verileri analiz edildiğinde mikrosatellit stabil(MSS) olan
hastaların medyan hastalıksız sağkalım süresi 39,8 ay iken mikrosatellit
instabil(MSI) olan hastaların medyan hastalıksız sağkalım süresine ulaşılamadı,
istatiksel olarak p değeri henüz anlamlılığa ulaşamamış olsa da beklenen bir
anlamlılık sözkonusudur. Tüm hastaların medyan genel sağkalım süresi 111,6 ay
(93,0-130,1). Evre 2 hastaların medyan genel sağkalım süresi 134,8 ay (120,4-149,1),
evre 3 hastaların medyan genel sağkalım süresi 74,0 ay (64,9-83,2) saptandı. Evre 2
hastalarda medyan genel sağkalım süresi istatiksel olarak daha fazla bulundu
(p< 0,001). Patoloji raporlarından elde edilen lenfovasküler-perinöral invazyon
bilgisine göre LVİ-PNİ saptanan hastaların medyan genel sağkalım süresi 48,7 ay
(43,2-54,1) iken LVİ-PNİ olmayan hastaların medyan genel sağkalım süresi 108,5 ay
(47,7-169,3) saptandı ve istatiksel olarak anlamlı idi (p=0,002). MS durumu ve genel
sağkalım veri analizinde MSS olan hastaların ortalama genel sağkalım süresi 43,8 ay
(34,7-52,9) iken MSI olan hastaların ortalama genel sağkalım süresi 63,0 ay (12,2-
113,8) hesaplandı ancak istatiksel olarak anlamlı fark saptanmadı (p=0,513).
Adjuvan kemoterapi alan ve almayan hastaların genel sağkalım süreleri
incelendiğinde adjuvan KT alan hastaların medyan genel sağkalım süresi 122,8 ay
(100,0-145,6) iken adjuvan KT almayan hastaların 97,0 ay (45,0-149,0) olup klinik 
olarak anlamlı ancak istatiksel olarak anlamlı fark saptanmadı (p=0,318). MS
durumu ile cinsiyet analiz edildiğinde 53 erkek hastadan 33'ünde (%62,3) MSS iken
20 hastada (%37,7) MSI idi. 35 kadın hastadan 29'unda (%82,9) MSS saptanırken 6
hastada (%17,1) MSI saptandı (p=0,038). Patoloji verilerinden erken evre 39
hastanın ve metastatik 29 hastanın MS durumu incelendi. Erken evre hastaların 25'i
(%64,19) MSS, 14 hasta (%35,9) MSI idi. Metastatik hastaların 24'ü (%82,8) MSS
iken 5 hastada (%17,2) MSI saptandı (p=0,090). Grade ile MS durumu analizinde 43
hastanın verilerine ulaşıldı. Grade 1 hastaların 14'ü (%77,8) MSS iken, 4 hastada
(%22,2) MSI idi, grade 2 hastaların 12'si (%54,5) MSS iken 10 hastada (%45,5) MSI
idi, grade 3 hastaların 1'i (%33,3) MSS iken 2 hastada (%66,7) MSI idi (p=0,175).
MS durumu ile tümör lokalizasyonu verilerinde 66 hasta analiz edildi. 45 sol kolon
tümöründen 34'ünde (%75,6) MSS iken 11'inde (%24,4) MSI saptandı. 21 sağ kolon
tümöründen 12'sinde (%57,1) MSS iken 9'unda (%42,9) MSI saptandı (p=0,130).
Evre 2 hastalar risk faktörlerine göre analiz edildiğinde yüksek risk faktörü olmayan
hastaların medyan hastalıksız sağkalım süresi 161,1 ay (105,5-216,7) iken yüksek
risk faktörü olan hastaların medyan hastalıksız sağkalım süresi 38,6 ay (25,6-51,7)
hesaplandı ve istatiksel olarak anlamlı fark bulundu (p=0,002). Genel sağkalım
açısından yüksek risk faktörü olmayan hastaların medyan genel sağkalım süresi
161,1 ay (146,7-175,5) iken yüksek risk faktörü olan hastaların medyan genel
sağkalım süresi 77,9 ay (20,8-135,8) hesaplandı ve istatiksel olarak anlamlı fark
bulundu (p=0,003). Evre 2 hastalardan yüksek risk faktörlerinden lenfovaskülerperinöral invazyon ile adjuvan kemoterapi durumunun hastalıksız sağkalım üzerine
etkisi incelendiğinde lenfovasküler-perinöral invazyonu olup adjuvan kemoterapi
alan hastaların ortalama hastalıksız sağkalım süresi 53,3 ay (13,8-92,8) iken adjuvan
kemoterapi almayan hastaların ortalama hastalıksız sağkalım süresi 22,2 ay (3,7-
40,0) hesaplandı. Lenfovasküler-perinöral invazyonu olmayan hastalar içinde
adjuvan kemoterapi alan hastaların ortalama genel sağkalım süresi 100,5 ay (76,3-
124,8) iken adjuvan kemoterapi almayan hastaların ortalama hastalıksız sağkalım
süresi 115,9 ay (96,5-135,3) hesaplandı ve istatiksel olarak anlamlı fark bulundu
(p=0,001).
Sonuç: Çalışmamızda da evre 2 hastaların hastalıksız ve genel sağkalım süreleri evre
3 hastalara göre daha uzun bulunmuştur. Adjuvan kemoterapi alan hastaların genel 
sağkalım süreleri kemoterapi almayan hastalara göre daha uzun olup klinik
anlamlılığa sahipti. Çalışmamızda evre 2 hastalarda lenfovaküler ve perinöral
invazyonun prognostik faktörler olduğu gösterilmiş olup varlığı daha kısa sağkalım
sürelerine neden olmaktadır. Ayrıca evre 2 hastalarda LVİ-PNİ olan yüksek riskli
grupta adjuvan kemoterapi verilmesi hem hastalıksız hem de genel sağkalım
sürelerini uzatmaktaydı. MSI durumunun sağkalıma üzerine etkisi bakımından halen
medyan hastalıksız sağkalım süresine ulaşılmamış olup ve istatiksel olarak beklenen
bir anlamlılık sözkonusudur.

Abstract:
Purpose: Colorectal cancers are the 3rd most common malignancy worldwide.
Although adjuvant chemotherapy is used as a standard treatment for stage 3 patients,
it is not given to all stage 2 patients. Adjuvant chemotherapy is given to patients with
high risk factors for stage II colorectal cancer. The most important prognostic factor
in colorectal cancer is the stage of the disease. High risk markers in stage II are T4
primary; high grade poorly differentiated histology (signet ring cell, mucinosis
tumor), lymphovascular invasion (LVI), perineural invasion (PNI), bowel obstruction
and / or perforation closed (including perforation), surgical margin positivity, 12 or
less lymph nodes in surgical specimens dissection, high preoperative CEA level (>
5). In addition, microsatellite status is accepted as an important prognostic value used
for adjuvant chemotherapy evaluation. In our study, we analyzed the prognostic
importance and survival relationships of these risk factors, including microsatellite
instability, in patients with colorectal cancer.
Method: In this study, 388 patients with early stage (stage 2-3) colorectal cancer
who applied to Dicle University Medical Faculty Hospital Oncology Department
between 2001-2020 and 58 patients (metastatic and nonmetastatic) whose MS status
data were examined were included retrospectively. The data of the patients were
accessed via HBYS (Hospital Information Management System). Disease-free
survival and overall survival status according to age, gender, stage, pathologically T
stage, N stage, grade, lymphovascular-perineural invasion information, tumor
location, adjuvant chemotherapy and MSS / MSI (Microsatellite stable /
Microsatellite unstable) status analyzed.
Results: Of the 388 patients included in the study, 199 (51.3%) were male, 189
(48.7%) were female, 246 (59%) were stage 2 and 142 (42%) were stage 3. In terms
of tumor localization, 314 (81.3%) patients were located in the left colon, while 72
(18.7%) patients were located in the right colon. Of these, 186 (48.2%) were located
in the rectum, 128 (33.2%) in the sigmoid colon, 46 (11.9%) in the ascending colon, 
and 26 (6.7%) in the transverse colon. Median disease-free survival of all patients
was 91.7 months (64.3-119.2). The median disease-free survival time of stage 2
patients was 135.7 months (107-164.5), and the median disease-free survival time of
stage 3 patients was 47 months (27.8-67.3). Median disease-free survival time was
statistically higher in stage 2 patients (p < 0.001). While 281 of the patients (78.4%)
received adjuvant chemotherapy, 77 (21.5%) of them were not given adjuvant
chemotherapy and treatment information of the remaining patients could not be
reached. While 166 (72.8%) of stage 2 patients received adjuvant chemotherapy, 62
(27.2%) of them did not receive chemotherapy, while 122 (87.7%) of stage 3 patients
received adjuvant chemotherapy treatment, 17 (12.3%) ) the patient did not receive
adjuvant chemotherapy. In stage 2 and stage 3 patients, disease-free survival was 111
months in those who received adjuvant chemotherapy, while it was 79 months in
those who did not, but there was no statistical significance (p = 0,5). According to
the lymphovascular-perineural invasion (LVI-PNI), which is one of the risk factors,
the average disease-free survival time of the patients was 54.6 months (30.3-78.9),
while the mean disease-free survival time of patients without LVI-PNI was 94.1
months (74.4) -113.8) and it was statistically significant (p = 0.015). When
microsatellite (MS) status and disease-free survival data were analyzed, the median
disease-free survival time of patients with microsatellite (CNS) stable (CNS) was
39.8 months, while the median disease-free survival time of patients with
microsatellite (MSI) instability could not be reached, although statistically the p
value has not reached significance yet, there is an expected significance. Median
overall survival of all patients was 111.6 months (93.0-130.1). The median overall
survival time of stage 2 patients was 134.8 months (120.4-149.1), and the median
overall survival time of stage 3 patients was 74.0 months (64.9-83.2). Median overall
survival time was found to be statistically higher in stage 2 patients (p <0.001).
According to lymphovascular-perineural invasion information obtained from
pathology reports, the median overall survival time of patients with LVI-PNI was
48.7 months (43.2-54.1), while the median overall survival of patients without LVIPNI was 108.5 months (47.7) -169.3) and it was statistically significant (p = 0.002).
In the MS status and overall survival data analysis, the mean overall survival time of
patients with CNS was 43.8 months (34.7-52.9), while the mean overall survival time 
of patients with MSI was 63.0 months (12.2-113.8), but No statistically significant
difference was found (p = 0.513). When the overall survival times of patients who
received and did not receive adjuvant chemotherapy were examined, the median
overall survival time of patients who received adjuvant chemotherapy was 122.8
months (100.0-145.6), while patients who did not receive adjuvant chemotherapy
were 97.0 months (45.0-149.0). There was no clinically significant but statistically
significant difference (p = 0.318). When MS status and gender were analyzed, it was
MSS in 33 (62.3%) of 53 male patients and MSI in 20 patients (37.7%). MSS was
detected in 29 (82.9%) of 35 female patients, while MSI was detected in 6 patients
(17.1%) (p = 0.038). Among the pathology data, the MS status of 39 early-stage
patients and 29 metastatic patients were analyzed. 25 (64.19%) of the early stage
patients were MSS and 14 (35.9%) were MSI. While 24 (82.8%) of metastatic
patients were MSS, MSI was detected in 5 patients (17.2%) (p = 0.090). Data of 43
patients were obtained in MS status analysis with grade. While 14 (77.8%) of grade 1
patients were MSS, 4 patients (22.2%) were MSI, while 12 (54.5%) of grade 2
patients were MSS, 10 patients (45.5%) were MSI, while 1 (33.3%) of the grade 3
patients was MSS, 2 patients (66.7%) were MSI (p = 0.175). 66 patients were
analyzed for MS status and tumor localization data. Of the 45 left colon tumors, 34
(75.6%) were MSS, while 11 (24.4%) had MSI. Of the 21 right colon tumors, 12
(57.1%) were MSS, while 9 (42.9%) had MSI (p = 0.130). When stage 2 patients
were analyzed according to risk factors, the median disease-free survival time of
patients without high risk factors was 161.1 months (105.5-216.7), while the median
disease-free survival time of patients with high risk factors was 38.6 months (25.6-
51). , 7), and a statistically significant difference was found (p = 0.002). The median
overall survival time of patients without high risk factors for overall survival was
161.1 months (146.7-175.5), while the median overall survival time for patients with
high risk factors was 77.9 months (20.8-135.8), and There was a statistically
significant difference (p = 0.003). When the effect of lymphovascular-perineural
invasion and adjuvant chemotherapy status on disease-free survival was examined in
stage 2 patients, the mean disease-free survival time of patients with
lymphovascular-perineural invasion who received adjuvant chemotherapy was 53.3
months (13.8-92.8), while patients who did not receive adjuvant chemotherapy The 
average disease-free survival time was 22.2 months (3.7-40.0). Among patients
without lymphovascular-perineural invasion, the mean overall survival time of
patients who received adjuvant chemotherapy was 100.5 months (76.3-124.8), while
the mean disease-free survival time of patients not receiving adjuvant chemotherapy
was 115.9 months (96.5-135.3). was calculated and a statistically significant
difference was found (p = 0.001).
Conclusion: In our study, disease-free and overall survival was longer in stage 2
patients compared to stage 3 patients. The overall survival of patients who received
adjuvant chemotherapy was longer than those who did not receive chemotherapy,
and had clinical significance. In our study, it has been shown that lymphovacular and
perineural invasion are prognostic factors in Stage 2 patients, and their presence
causes shorter survival times. In addition, adjuvant chemotherapy in stage 2 patients
with high risk group with LVI-PNI prolonged both disease-free and overall survival.
In terms of the effect of MSI status on survival, the median disease-free survival time
has not been reached yet, and there is a statistically expected significance.