Hubungan Peningkatan Kadar Interleukin-6 Serum Post Kemoterapi Pertama Terhadap Kejadian Chemotherapy Induced Peripheral Neuropathy pada Kanker Payudara Non-Metastatik yang Menjalani Kemoterapi Berbasis Taxane

Ridha Niradita Widyasari, dr. Susanna Hilda Hutajulu, Ph.D, SpPD-KHOM.; dr. Mardiah Suci Hardianti, Ph.D, SpPD-KHOM

2025 | Tesis-Subspesialis | SUBSPESIALIS ILMU PENYAKIT DALAM

Latar  Belakang: Chemotherapy induced peripheral neuropathy (CIPN) adalah salah satu efek samping kemoterapi. CIPN dapat menyebabkan gangguan pada fungsi sensorik, motorik dan otonom sehingga mengganggu aktivitas, menyebabkan terapi kanker tidak optimal dan mempengaruhi kualitas hidup jangka panjang pasien. Beberapa studi menunjukkan peran inflamasi pada proses kejadian CIPN. Interleukin-6 (IL-6) merupakan salah satu mediator inflamasi pada kanker payudara dan berperan pada proses kejadian CIPN. Namun hubungan sitokin tersebut terhadap kejadian CIPN post kemoterapi pertama dan kumulatif pada kanker payudara non-metastatik belum banyak dievaluasi.

Metode: Sebanyak 97 pasien yang baru terdiagnosis kanker payudara non-metastatik sejak Juli 2018 hingga Juni 2020 diikutkan dalam penelitian ini. Dilakukan pengukuran kadar IL-6 serum pre kemoterapi dan post kemoterapi pertama dengan menggunakan metode ELISA. Dilakukan penilaian evaluasi CIPN di setiap siklus kemoterapi dengan skor Common Terminology Criteria for Adverse Events (CTCAE). Kejadian CIPN didokumentasi sebagai CIPN post kemoterapi pertama dan CIPN yang terjadi setiap siklus sampai kemoterapi selesai (kumulatif). Hubungan peningkatan median IL-6 post kemoterapi pertama terhadap kejadian CIPN post kemoterapi pertama dan kumulatif dianalisis dengan wilcoxon. IL-6 pre kemoterapi dikategorikan sebagai ? 0 pg/ml dan > 0 pg/ml. IL-6 post kemoterapi pertama dikategorikan sebagai ? 0,89 pg/ml dan > 0,89 pg/ml. IL-6 post kemoterapi pertama, faktor demografi dan klinikopatologi yang mempengaruhi resiko kejadian CIPN post kemoterapi pertama dan kumulatif dianalisis univariat dengan uji Chi- Square atau uji Fisher’s Exact’s. Hasil analisis univariat dengan nilai   p<0>

Hasil: Terdapat peningkatan signifikan nilai median IL-6 post kemoterapi pertama dibandingkan pre kemoterapi (0, 89 pg/ml vs 0 pg/ml, p=0,000). Kejadian CIPN post kemo pertama terjadi pada 18 pasien (18,6 %) sedang kejadian CIPN kumulatif terjadi pada 88 pasien (88,7%). Sebanyak 55 (51,3%) pasien mengalami onset baru CIPN dan 2 pasien mengalami progresivitas (2,3%) selama program kemoterapi. Perubahan nilai median IL-6 post kemoterapi pertama meningkat signifikan baik pada kelompok CIPN post kemoterapi pertama maupun yang tidak CIPN (p=0,018 dan p=0,000). Perubahan nilai median IL-6 post kemoterapi pertama meningkat signifikan pada kelompok yang mengalami CIPN kumulatif (p=0,000), namun meningkat tidak bermakna pada kelompok non CIPN kumulatif (p=0,110). Pada kelompok pasien yang mengalami CIPN post kemoterapi pertama terdapat 4 orang (22,2%) dengan peningkatan IL-6 pre kemoterapi(>0 pg/ml) dan 14 pasien (77,8%) dengan penurunan IL-6, serta terdapat 6 orang (33,3%) dengan peningkatan IL-6 pre kemoterapi(>0,89 pg/ml) dan 12 pasien (66,7%) dengan penurunan IL-6. Pada kelompok pasien yang mengalami CIPN kumulatif didapatkan 19 pasien (21,6%) dengan peningkatan IL-6 pre kemoterapi (>0 pg/ml) dan 69 pasien (78,4%) dengan penurunan IL-6 pre kemoterapi, serta terdapat 47 pasien (53,4%) dengan peningkatan IL-6 post kemoterapi pertama (>0,89 pg/ml) dan 41 pasien (46,6%)dengan penurunan IL-6 post kemoterapi pertama. Dalam analisis multivariat, peningkatan IL-6 post kemoterapi pertama tidak berhubungan terhadap kejadian CIPN baik post kemoterapi pertama maupun CIPN kumulatif (odds ratio (OR) OR 0,449; 95% IK 0,150-1,343; p = 0,152 dan OR 4,695, 95%. IK 00,797-27,668; p =0,087)

Simpulan: Terdapat peningkatan signifikan median IL-6 post kemoterapi pertama dibandingkan pre kemoterapi. Proporsi perubahan nilai median ini secara signifikan terjadi baik pada pasien yang menderita CIPN post kemoterapi pertama, pasien non CIPN post kemoterapi pertama, serta pasien CIPN kumulatif. Namun demikian, dalam analisis multivariat, peningkatan kadar IL-6 post kemoterapi pertama tidak menunjukkan hubungan signifikan terhadap kejadian CIPN pada subjek penelitian ini, baik CIPN post kemoterapi pertama maupun CIPN kumulatif.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy. CIPN can cause impairments in sensory, motor, and autonomic functions, leading to disruptions in daily activities, suboptimal cancer treatment, and long-term reductions in patients' quality of life. Several studies have suggested that inflammation plays a role in the pathogenesis of CIPN. Interleukin-6 (IL-6) is an inflammatory mediator involved in breast cancer and is implicated in the development of CIPN. However, the relationship between this cytokine and the occurrence of early and cumulative CIPN in non-metastatic breast cancer patients has not been extensively evaluated

Methods: This study included 97 newly diagnosed non-metastatic breast cancer patients between July 2018 and June 2020. Serum IL-6 levels were measured pre- chemotherapy and after the first chemotherapy cycle using the ELISA method. CIPN was evaluated at each chemotherapy cycle using the Common Terminology Criteria for Adverse Events (CTCAE) scoring system. CIPN incidence was recorded as early CIPN (post-first chemotherapy) and cumulative CIPN (occurring at any cycle until chemotherapy completion). The association between median IL-6 changes before and after the first chemotherapy cycle with early and cumulative CIPN incidence was analyzed using the Wilcoxon test. C Pre-chemotherapy IL-6 levels were categorized as ? 0 pg/mL and > 0 pg/mL. Post-first-cycle chemotherapy IL-6 levels were categorized as ? 0.89 pg/mL and > 0.89 pg/mL. Post-first-cycle IL-6 levels, along with demographic and clinicopathological factors associated with the risk of chemotherapy-induced peripheral neuropathy (CIPN) after the first cycle and cumulatively, were analyzed using univariate analysis via the Chi-Square testor Fisher’s Exact test. Variables with a p-value < 0>

Results: There was a significant increase in median serum IL-6 levels after the first chemotherapy cycle compared to pre-chemotherapy levels (0.89 pg/mL vs. 0 pg/mL, p = 0.000). Early CIPN occurred in 18 patients (18.6%), while cumulative CIPN was observed in 88 patients (88.7%). Fifty-five patients (51.3%) experienced new-onset CIPN, and 2 patients (2.3%) showed progression of neuropathy during chemotherapy program. The increase in median IL-6 levels after the first chemotherapy cycle was significant in both the early CIPN group and the non-CIPN group (p = 0.018 and p = 0.000, respectively). Median IL-6 levels also increased significantly in the cumulative CIPN group (p = 0.000), but the increase was not statistically significant in the non-cumulative CIPN group (p = 0.110). In the group of patients who developed CIPN after the first cycle of chemotherapy, 4 patients (22.2%) had elevated pre-chemotherapy IL-6 levels (>0 pg/mL), while 14 patients (77.8%) had decreased IL-6 levels. Additionally, 6 patients (33.3%) had elevated post-chemotherapy IL-6 levels (>0.89 pg/mL), and 12 patients (66.7%) had decreased IL-6 levels. Among patients who experienced cumulative CIPN, 19 patients (21.6%) had elevated pre-chemotherapy IL-6 levels (>0 pg/mL), while 69 patients (78.4%) had decreased levels. Furthermore, 47 patients (53.4%) exhibited elevated post-first-cycle IL-6 levels (>0.89 pg/mL), whereas 41 patients (46.6%) showed decreased levels. In multivariate analysis, increased IL-6 levels after the first chemotherapy cycle were not significantly associated with the occurrence of either post-first-cycle CIPN or cumulative CIPN (odds ratio [OR] 0.449; 95% confidence interval [CI]: 0.150–1.343; p = 0.152, and OR 4.695; 95% CI: 0.797–27.668; p = 0.087, respectively).

Conclusion:This study demonstrated a significant increase in median IL-6 levels following the first cycle of chemotherapy compared to pre-chemotherapy levels. The proportion of this change in median values was statistically significant across all patient subgroups, including those who developed chemotherapy-induced peripheral neuropathy (CIPN) after the first cycle, those who did not develop CIPN, and those with cumulative CIPN. However, in the multivariate analysis, elevated IL-6 levels after the first chemotherapy cycle were not significantly associated with the occurrence of CIPN in this study population, either after the first chemotherapy cycle or cumulatively.

Kata Kunci : kanker payudara, IL-6, inflamasi, CIPN