The 25th European Congress of Obstetrics and Gynecology Neoadjuvant chemotherapy with Paclitaxel, Cisplatin and Bevacizumab for advanced cervical cancer Takuji Ueno, Shinji Monoe, Yu Yaegashi, Takuma Yamada, Takehiko Takeda, Sho Tano, Kaname Uno, Michinori Mayama, Mayu Ukai, Teppei Suzuki, Yasuyuki Kishigami and Hidenori Oguchi The Department of Obstetrics and Gynecology, TOYOTA Memorial Hospital, Aichi, Japan

Introduction Concurrent chemoradiotherapy (CCRT) and radical hysterectomy (RH) are the standard treatment of cervical cancer1). They often associated with significant complications such as bladder dysfunction, and reduce patients’ quality of life. Nerve sparing RH (NSRH) that remains hypogastric plexus and bladder branches is said to reduce bladder dysfunction. 1) Cervical Cancer Guideline(Version 1. 2016). NCCN Crinical Practice Guidelines in Oncology

Introduction Recently, the utility of Bevacizumab, a vascular endothelial growth factor monoclonal antibody, has been reported in advanced cervical cancer2). Some reports show neoadjuvant　chemotherapy with conventional regimen followed by RH is valid3). 2) Tewari KS, et al. N Engl J Med. 2014; 370: 734-43 3) Pierluigi BP, et al. Annals of Surgical Oncology 14(9):2643–2648

Objective The aim of this study is to analyze the feasibility and efficacy of neoadjuvant chemotherapy with Bevacizumab followed by NSRH in patients with advanced cervical cancer.

Material & Method Between 2016 and 2017, patients with advanced cervical cancer were enrolled in this study. Patients who had a bulky cervical mass over 4 cm, took neoadjuvant chemotherapy, Paclitaxel, Cisplatin, and Bevacizumab (TPB) treatment followed by NSRH were enrolled.

Material & Method When TPB treatment was feasible, that was continued 3 courses before NSRH. After operation we analyzed complications, response in pathological findings and bladder dysfunction at one month. We evaluated the efficacy of TPB treatment by serous SCC levels, ultrasound and magnetic resonance imaging (MRI).

Patients Case Age Stage Size (cm) SCC (ng/mL) Pathological Type 1 67 ⅡB 4.0 2 SCC 56 4.6 2.8 3 73 5.6 27.6 4 47 ⅢB 6.0 18.7 5 68 4.7 1.2 6 61 ⅣB 6.3 19.8

Results Stage ⅡB ⅢB ⅣB Case Size (cm) First → TPB x 3 SCC (ng/mL) Effect (MRI) 1 ⅡB 4.0　→　0.0 2.0 → 1.2 CR 2 4.6　→　1.8 2.8 → 1.0 PR 3 5.6　→　0.6 27.6 → 1.9 4 ⅢB 6.0　→　0.7 18.7 → 0.8 5 4.7　→　0.5 1.2 → 0.6 6 ⅣB 6.3　→　0.6 19.8 → 1.0 CR : Complete Response PR : Partial Response

Case 1 (StageⅡB) Before Therapy After TPBx3 Yajirusi

Case 1 (StageⅡB)

Results Stage ⅡB ⅢB ⅣB Case Size (cm) First → TPB x 3 SCC (ng/mL) Effect (MRI) 1 ⅡB 4.0　→　0.0 2.0 → 1.2 CR 2 4.6　→　1.8 2.8 → 1.0 PR 3 5.6　→　0.6 27.6 → 1.9 4 ⅢB 6.0　→　0.7 18.7 → 0.8 5 4.7　→　0.5 1.2 → 0.6 6 ⅣB 6.3　→　0.6 19.8 → 1.0 CR : Complete Response PR : Partial Response

Case 4 (StageⅢB) Before Therapy After TPBx3

Results Stage ⅡB ⅢB ⅣB Case Size (cm) First → TPB x 3 SCC (ng/mL) Effect (MRI) 1 ⅡB 4.0　→　0.0 2.0 → 1.2 CR 2 4.6　→　1.8 2.8 → 1.0 PR 3 5.6　→　0.6 27.6 → 1.9 4 ⅢB 6.0　→　0.7 18.7 → 0.8 5 4.7　→　0.5 1.2 → 0.6 6 ⅣB 6.3　→　0.6 19.8 → 1.0 CR : Complete Response PR : Partial Response

Case 6 (StageⅣB) Before Therapy After TPBx3

Case 6 (StageⅣB) Before Therapy After TPBx3

Results Stage ⅡB ⅢB ⅣB Case Size (cm) First → TPB x 3 SCC (ng/mL) Effect (MRI) 1 ⅡB 4.0　→　0.0 2.0 → 1.2 CR 2 4.6　→　1.8 2.8 → 1.0 PR 3 5.6　→　0.6 27.6 → 1.9 4 ⅢB 6.0　→　0.7 18.7 → 0.8 5 4.7　→　0.5 1.2 → 0.6 6 ⅣB 6.3　→　0.6 19.8 → 1.0 All patients underwent 3 courses TPB, and accomplished NSRH. In all cases the chemotherapy reduced the size of tumor remarkably. SCC decreased in all cases.

Case 6 裏はべつになくても 17

Bafore Therapy Squamaous Cell Carcinoma Case 6 Bafore Therapy Squamaous Cell Carcinoma

Case 6 Residual Tumor 19

Results Two patients achieved pathological CR Case Size (cm) First → TPB x 3 SCC (ng/mL) Effect (MRI) (Patho) 1 4.0　→　0.0 2.0 → 1.2 CR pCR 2 4.6　→　1.8 2.8 → 1.0 PR pPR 3 5.6　→　0.6 27.6 → 1.9 4 6.0　→　0.7 18.7 → 0.8 5 4.7　→　0.5 1.2 → 0.6 6 6.3　→　0.6 19.8 → 1.0 P強調 Two patients achieved pathological CR The other 4 patients achieved clinical and pathological PR

Results Two patients achieved pathological CR Case Size (cm) First → TPB x 3 SCC (ng/mL) Effect (MRI) (Patho) 1 4.0　→　0.0 2.0 → 1.2 CR pCR 2 4.6　→　1.8 2.8 → 1.0 PR pPR 3 5.6　→　0.6 27.6 → 1.9 4 6.0　→　0.7 18.7 → 0.8 5 4.7　→　0.5 1.2 → 0.6 6 6.3　→　0.6 19.8 → 1.0 P強調 Two patients achieved pathological CR The other 4 patients achieved clinical and pathological PR

Side Effects Two patients (case 1,4) complicated gastro-duodenum ulcer, and one patient (case 1) got pulmonary embolism a few days after operation. No other major side effect of Bevacizmab has occurred. No patient got bladder dysfunction one month after the operation.

Discussion 1 : Efficacy The additional effect of chemotherapy with Bevacizumab was proved by GOG-0240 study2). In our all cases, TPB treatment reduced the size of tumor remarkably, and NSRH was feasible. Two of them achieved pathological CR.

Discussion 2 : Side Effects Gastrointestinal or genitourinary fistula is major side effect of Bevacizumab. It is reported that thromboembolic events and hypertension are increased with Bevacizumab containing chemotherapy. We experienced two gastrointestinal ulcer, and one pulmonary embolism, but they were cured with medication.

Discussion 3 : Operation After RH, bladder dysfunction is common complication developed in about 70% of the patients and usually resolves within 6-12 months4)5). NSRH is valid for reducing bladder dysfunction and keep the efficacy and oncology safety6). In our 6 cases, all patients’ bladder dysfunction improved in one month. 4) Chanita K, et al. Int Urogynecol J (2014) 25:91–96 5) Chen GD, et al. Gynecol Oncol (2002) 85:292–297 6) Ju-Won R, et al J Gynecol Oncol Vol. 26, No. 2:90-99

Conclusion TPB treatment followed by NSRH for advanced cervical cancer was reasonable. In addition, TPB treatment reduced bladder dysfunction, and improved quality of life. We must be careful of complications of chemotherapy and operation. Long term follow-up should be conducted.

Thank You Teşekkürler