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Taipei Veterans General Hospital Practice Guideline for Cervical Cancer (2008) Huahsi Wu

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Clinical practice guidelines (CPG) CPG are systematically developed statements to assist practitioners and consumer decisions about appropriate health care for specific clinical circumstances . They are tools used by healthcare professionals to assist in clinical decision making and to improve healthcare for consumers. [Ref:New Zealand Guidelines Group (NZGG). Handbook for the preparation of explicit evidence-based clinical practice guidelines, 2001.p4 ]

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(guideline) (To make evidence based standards explicit and accessible) (To make decision making easier and more objective) (To educate patients and professionals about current best practice) (To improve the cost effectiveness of health services) (To serve as a tool for external control)

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Clinical Practical Guidelines Development Process

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Taipei Veterans General Hospital Practice Guideline for Cervical Cancer (I) FIGO early stage (IA to IIA, selected IIB) (II) FIGO easrly stage inoperable patients (III) and advanced stage (IV) Incidental cervical cancer (post simple hysterectomy) (V) Persistent/Recurrent cervical cancer (VI) Chemotherapy

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( I ) FIGO early stage ( IA to IIA, selective IIB) StageTreatment Plan 5 year Survival Rate IA1 4cm) Radical hysterectomy + PLND + PALNS CCRT (Point A 75-85 Gy) Neoadjuvant Chemotherapy + Radical hysterectomy + PLND + PALNS 40-60% BSO considered if age > 50 y/o, adenocarcinoma, and poorly differentiated Ovarian transposition during RAH if adjuvant radiotherapy considered (age < 40 y/o)

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Post-operative Adjuvant Therapy (FIGO early stage) LN ParametriumBulky size ( - ) LVSI ( - ) / DSI ( - )Observation LVSI ( + ) and / or DSI ( + ) Observation R/T ( + ) Obsertvation R/T ( + )( - ) or ( + ) CCRT (see below) R/T ( + )( - ) or ( + ) CCRT (see below) Chemotherapy (see below) R/T If vaginal cut end ( + ) additional radiotherapy required Prognostic Risk Factors: - High Risk: LN (+) / Parametrial margin (+) / Vaginal cut end margin (+). - Intermediate Risk: Bulky tumor size ( > 4 cm ) / LVSI (+) / DSI (+) - Others Age / Diploidy / Differentiation / Histological Type

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( II ) FIGO early stage inoperable patients and advanced stage ( 5 year survival rate: IIB-IVA: 20-60%, IVB: < 20 % ) Step 1 Lymph Node Assessment - Image study (CT scan, MRI or PET ) +/- FNA - Surgical staging (laparotomic, extra-peritoneal, or laparoscopic lymph node sampling ) Step 2 Lymph Node ( - ) - CCRT (platinum-based chemotherapy) Para-aortic boost (Point A 85Gy) Lymph Node ( + ) - CCRT (platinum-based chemotherapy) + Para-aortic boost (Point A 85Gy) Step 3 Consolidation chemotherapy, if necessary

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(III) Incidental Cervical Cancer ( Post Simple Hysterectomy ) Stroma Invasion LVSIManagement Depth < 3 mm ( - ) Observation ( + ) See below Stroma Invasion Surgical Margin LN status (Image study) ManagementAdjuvant Tx Depth < 3 mm with LVSI (+) or Depth 3mm ( - ) Re-op* R/T According to pathological risk factors ( see above ) ( + ) LND + CCRT Re-op* CCRT (see below) ( + ) ( - ) R/T CCRT (see below) Re-op* ( + ) LND + CCRT Re-op* CCRT (see below)

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(III) Incidental Cervical Cancer ( Post Simple Hysterectomy ) Re-op include the following: Radical parametrectomy + Upper vaginectomy + PLND PALNS Image study consistent with the following: No parametrium invasion No pelvic side wall invasion No rectal or bladder invasion ----

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(IV) Treatment Strategies for Persistent / Recurrent Cervical Cancer Factors to Consider: Site of recurrence or metastases Pelvic: central, side wall, combined Extra-pelvic: intra-abdominal organs, Distant lymph nodes, Distant disseminated metastasis Prior therapy Surgery Radiotherapy Radiotherapy Surgery Status of patient's performance Palliative or Curative treatment

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(IV-1) Cervical Cancer with Central Recurrence Prior Surgery Surgical intervention if no contraindication Radiotherapy if surgical intervention not possible Prior Radiotherapy Surgical intervention if no contraindication Radiotherapy indicated if recurrence outside of previously treated field Palliative radiotherapy or palliative chemotherapy Surgical Intervention If previous surgery is only total abdominal hysterectomy Radical parametrectomy + PLND + PALNS If previous surgery is radical hysterectomy + PLND + PALNS Exenteration can be considered ( Total / Anterior / Posterior ).

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** Pelvic Exenteration Exenterative surgery should NOT be used as a palliative treatment, except in the presence of malignant fistulas in the pelvis. Final intraoperative assessment: The final decision to proceed with exenteration will not be made until the abdomen has been opened and assessment of the pelvic side-wall and posterior abdominal wall has been made, utilizing frozen section where necessary Contra-indications: * TRIAD: 1. Unilateral uropathy, non-functional kidney, or ureteric obstruction 2. Unilateral leg edema 3. Sciatic leg pain Absolute ContraindicationRelative Contraindication - Metastases to extrapelvic LN - Obesity - Metastases to abdominal viscera - Pelvic side-wall spread: direct extension or nodal metastases - Metastases to lung or bones - Triad *

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(IV-2) Cervical Cancer with Pelvic Side Wall Recurrence Prior Surgery Radiotherapy recommended Prior Radiotherapy Surgical intervention if no contraindication LEER procedure: laterally extended endopelvic resection CORT procedure: combined operative and radio-therapeutic treatment Indication: Histological confirmed, unifocal pelvic side-wall recurrence Free from tumor dissemination Tumor limited to a maximal diameter of < 5 cm Medical condition compatible with major surgery. Willingness to accept urinary or fecal diversion Palliative chemotherapy if surgical intervention not possible Radiotherapy indicated if recurrence outside of previously treated field Palliative radiotherapy or palliative chemotherapy

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(IV-3 ) Cervical Cancer with Central and Pelvic Side Wall Recurrence Prior Surgery Radiotherapy recommended Prior Radiotherapy Palliative chemotherapy Radiotherapy indicated if recurrence outside of previously treated field Palliative radiotherapy

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(IV-4) Only Distant LN Metastasis ( Including para-aortic LN ) Radiotherapy recommended Chemotherapy recommended ( see above ) CCRT recommended ( see above )

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(IV-5) Intra-abdominal Organ Metastasis Chemotherapy recommended ( see above ) Palliative surgery only for intestinal obstruction

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(IV-6) Dissemination Chemotherapy recommended ( see above )

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(V) Chemotherapy for Cx Ca Cisplatin is regarded as the most active agent in treating patients with cervical cancer and is recommended as first-linechemotherapy drug. In selective cases with poor renal function ( CCr < 60 ) Carboplatin can be substituted as an alternative drug

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Indications for Chemotherapy in Cervical Cancer Adjuvant chemotherapy for postoperative lymph node metastasis Neoadjuvant chemotherapy for bulky tumor Followed by surgery Followed by radiotherapy Concurrent chemoradiotherapy Early bulky tumor followed by surgery Postoperative with parametrium involvement and lymph node metastasis Local advanced cancer Consolidation chemotherapy after concurrent chemoradiotherapy for advanced cancer Palliative chemotherapy for distant, metastatic, or recurrent cancer If distant metastasis or recurrence Systemic Chemotherapy Palliative Radiotherapy

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(V-1) Neoadjuvant Chemotherapy Regimen Cisplatin Only (qw x 3 course) Cisplatin 40 mg/m 2 RH performed on 3rd day after completing chemotherapy POB Regimen (q3wk x 3 course) Cisplatin 50 mg/m 2 + Vincristine 1 mg/m 2 + Bleomycin 15 mg/m 2 (D1~3) RH performed within 3 weeks after completing chemotherapy TP Regimen (q10d x 3 course) Cisplatin 60 mg/m 2 + Palcitaxel 60 mg/m 2 (3hrs) RH performed within 3 weeks after completing chemotherapy

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(V-2) CCRT regimen Cisplatin Only (qw) Cisplatin 40 mg/m 2 POB Regimen (q3wk ) Cisplatin 50 mg/m 2 + Vincristine 1 mg/m 2 + Bleomycin 15 mg/m 2 (D1~3)

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(V-3) Consolidation Chemotherapy Regimen I+P regimen ( q3w ) 1. Cisplatin 50 mg/m 2 + Ifosfamide 1 gm/m 2 (3 days) 2. Cisplatin 50 mg/m 2 + Ifosfamide 5 gm/m 2 (24 hours)

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(V-4) Chemotherapy Regimen for Disseminated or Recurrent Disease 1. Squamous cell carcinomas 2. Non-squamous cell carcinomas

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Common used Regimen for Squamous Cell Carcinoma Cisplatin + Ifosfamide ( q3w ) Cisplatin 50 mg/m 2 + Ifosfamide 5 gm/m 2 (24 hours) Cisplatin + Ifosfamide ( D1~3) + Epirubicin ( q3w ) Cisplatin 50 mg/m 2 + Ifosfamide 1 gm/m 2 + Epirubicin 50 mg/m 2 Cisplatin + Ifosfamide (D1~3) + Paclitaxel ( q3w ) Cisplatin 50 mg/m 2 + Ifosfamide 1 gm/m 2 + Paclitaxel 175 mg/m 2 Cisplatin + Paclitaxel ( q3w ) Cisplatin 75 mg/m 2 + Paclitaxel 175 mg/m 2 Cisplatin + Topotecan (D1~3) ( q3w ) Cisplatin 50 mg/m 2 + Topotecan 1 mg/m 2 Cisplatin + Vincristine + Bleomycin (D1~3) ( q3w ) Cisplatin 50 mg/m 2 + Vincristine 1 mg/m 2 + Bleomycin 15 mg/m 2 Cisplatin + Gemcitabine Cisplatin 50 mg/m 2 (D1) + Gemzar 1000 mg/m 2 (D1 / D8) Cisplatin + Camptothecin Cisplatin: 75 mg/m 2 (D1) + CPT-11: 60mg/m 2 (D1 / D8 / D15)

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Common used Regimen for Non-squamous Cell Carcinoma Cisplatin + Paclitaxel ( q3w ) Cisplatin 75 mg/m 2 + Paclitaxel 175 mg/m 2 Paclitaxel ( q3w ) Paclitaxel 170 mg/m 2 ( 24 hrs ) Paclitaxel 135 mg/m 2 ( 24 hrs ) ( if prior radiotherapy ) Dose escalation to 200mg/m 2 or de-escalation to 110mg/m 2 depending on toxicity Etoposide ( every 28 days ) Oral Etoposide 50mg/m 2 /day for 21 days Oral Etoposide 40mg/m 2 /day ( if prior radiotherapy ) for 21 days Dose escalation to 60mg/m 2 /day depending on toxicity

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