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

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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]

(guideline)(To make evidence based standards explicit and accessible)

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(To educate patients and professionals about current best practice)

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Taipei Veterans General HospitalPractice Guideline for Cervical CancerFIGO early stage (IA to IIA, selected IIB)

FIGO easrly stage inoperable patients

and advanced stage

Incidental cervical cancer (post simple hysterectomy)

Persistent/Recurrent cervical cancer

Chemotherapy

( I ) FIGO early stage ( IA to IIA, selective IIB)

Post-operative Adjuvant Therapy (FIGO early stage) Prognostic Risk Factors: - High Risk: LN (+) / Parametrial margin (+) / Vaginal cut end margin (+). - Intermediate Risk: Bulky tumor size ( > 4 cm ) / LVSI (+) / DSI (+)- OthersAge / Diploidy / Differentiation / Histological Type

LNParametriumBulky size( - )( - )( - )LVSI ( - ) / DSI ( - )ObservationLVSI ( + ) and / or DSI ( + )ObservationR/T( + )ObsertvationR/T( + )( - ) or ( + )CCRT (see below)R/T( + )( - ) or ( + )( - ) or ( + )CCRT (see below)Chemotherapy (see below)R/TIf vaginal cut end ( + ) additional radiotherapy required

( II ) FIGO early stage inoperable patients and advanced stage ( 5 year survival rate: IIB-IVA: 20-60%, IVB: < 20 % )

(III) Incidental Cervical Cancer ( Post Simple Hysterectomy )

Stroma InvasionLVSIManagementDepth < 3 mm( - )Observation( + )See below

Stroma Invasion SurgicalMarginLN status(Image study)ManagementAdjuvant TxDepth < 3 mm with LVSI (+)orDepth 3mm( - )( - )Re-op*R/TAccording to pathologicalrisk factors( see above )( + )LND + CCRTRe-op*CCRT (see below)( + )( - )R/TCCRT (see below)Re-op*( + )LND + CCRTRe-op*CCRT (see below)

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

(IV) Treatment Strategies for Persistent / Recurrent Cervical Cancer Factors to Consider:Site of recurrence or metastasesPelvic: central, side wall, combinedExtra-pelvic: intra-abdominal organs, Distant lymph nodes, Distant disseminated metastasisPrior therapy Surgery Radiotherapy Radiotherapy SurgeryStatus of patient's performancePalliative or Curative treatment

(IV-1) Cervical Cancer with Central RecurrencePrior 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 ).

** Pelvic ExenterationExenterative 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 necessaryContra-indications:* TRIAD:1. Unilateral uropathy, non-functional kidney, or ureteric obstruction2. Unilateral leg edema3. Sciatic leg pain

(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

(IV-3 ) Cervical Cancer with Central and Pelvic Side Wall RecurrencePrior Surgery Radiotherapy recommended

Prior Radiotherapy Palliative chemotherapy Radiotherapy indicated if recurrence outside of previously treated field Palliative radiotherapy

(IV-4) Only Distant LN Metastasis ( Including para-aortic LN ) Radiotherapy recommended

Chemotherapy recommended ( see above )

CCRT recommended ( see above )

(IV-5) Intra-abdominal Organ Metastasis Chemotherapy recommended ( see above )

Palliative surgery only for intestinal obstruction

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

(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

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

(V-1) Neoadjuvant Chemotherapy RegimenCisplatin Only (qw x 3 course) Cisplatin 40 mg/m2 RH performed on 3rd day after completing chemotherapy

POB Regimen (q3wk x 3 course) Cisplatin 50 mg/m2 + Vincristine 1 mg/m2 + Bleomycin 15 mg/m2 (D1~3) RH performed within 3 weeks after completing chemotherapy

TP Regimen (q10d x 3 course)Cisplatin 60 mg/m2 + Palcitaxel 60 mg/m2 (3hrs) RH performed within 3 weeks after completing chemotherapy

(V-2) CCRT regimen Cisplatin Only (qw) Cisplatin 40 mg/m2

POB Regimen (q3wk ) Cisplatin 50 mg/m2 + Vincristine 1 mg/m2 + Bleomycin 15 mg/m2 (D1~3)

(V-3) Consolidation Chemotherapy Regimen I+P regimen ( q3w )Cisplatin 50 mg/m2 + Ifosfamide 1 gm/m2 (3 days)

Cisplatin 50 mg/m2 + Ifosfamide 5 gm/m2 (24 hours)

(V-4) Chemotherapy Regimen for Disseminated or Recurrent DiseaseSquamous cell carcinomas

Non-squamous cell carcinomas

Common used Regimen for Squamous Cell Carcinoma Cisplatin + Ifosfamide ( q3w ) Cisplatin 50 mg/m2 + Ifosfamide 5 gm/m2 (24 hours) Cisplatin + Ifosfamide ( D1~3) + Epirubicin ( q3w ) Cisplatin 50 mg/m2 + Ifosfamide 1 gm/m2 + Epirubicin 50 mg/m2 Cisplatin + Ifosfamide (D1~3) + Paclitaxel ( q3w ) Cisplatin 50 mg/m2 + Ifosfamide 1 gm/m2 + Paclitaxel 175 mg/m2 Cisplatin + Paclitaxel ( q3w ) Cisplatin 75 mg/m2 + Paclitaxel 175 mg/m2 Cisplatin + Topotecan (D1~3) ( q3w ) Cisplatin 50 mg/m2 + Topotecan 1 mg/m2 Cisplatin + Vincristine + Bleomycin (D1~3) ( q3w ) Cisplatin 50 mg/m2 + Vincristine 1 mg/m2 + Bleomycin 15 mg/m2 Cisplatin + Gemcitabine Cisplatin 50 mg/m2 (D1) + Gemzar 1000 mg/m2 (D1 / D8) Cisplatin + Camptothecin Cisplatin: 75 mg/m2 (D1) + CPT-11: 60mg/m2 (D1 / D8 / D15)

Common used Regimen for Non-squamous Cell Carcinoma Cisplatin + Paclitaxel ( q3w ) Cisplatin 75 mg/m2+ Paclitaxel 175 mg/m2 Paclitaxel ( q3w ) Paclitaxel 170 mg/m2 ( 24 hrs ) Paclitaxel 135 mg/m2 ( 24 hrs ) ( if prior radiotherapy ) Dose escalation to 200mg/m2 or de-escalation to 110mg/m2 depending on toxicityEtoposide ( every 28 days ) Oral Etoposide 50mg/m2/day for 21 days Oral Etoposide 40mg/m2/day ( if prior radiotherapy ) for 21 days Dose escalation to 60mg/m2/day depending on toxicity

GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence Worldwide. World Health Organization. 2004.Cervical Cancer, in National Comprehensive Cancer Network ( NCCN) Clinical Practice Guidelines in Oncology, v.1. 2006. http://www.nccn.org.Benedet JL, Bender H, Jones H, III, et al. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. International Journal of Gynecology & Obstetrics 2000; 70:209-262Cervical Cancer (PDQR): Treatment, Health Professional Version. National Cancer Institute. 2003.Resbeut M, Fondrinier E, Fervers B, et al. Standards, Options and Recommendations for the management of invasive cervical cancer patients ( non metastatic). Bulletin du Cancer 2003;90:333-346Resbeut M, Fondrinier E, Fervers B, et al. Carcinoma of the cervix. Br. J. Cancer 2001;84 Suppl 2:24-30.Landoni F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage Ib-II2 cervical cancer. Lancet 1997; 350:535-540.Chang TC, Lai CH, Hong JH, et al. Randomized trial of neoadjuvant cisplatin vincrinstine, bleomycin, and radical hysterectomy versus radiation therapy for bulky stage IB and IIa cervical cancer. J. Clin. Oncol. 2000. Apr; 18(8): 1740-1747.Neoadjuvant chemotherapy for locally advanced cervical cancer: a systemic review and meta-analysis of individual patient data from 21 randomised trials. European Journal of Cancer 2003; 39:2470-2486.Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIb- IVa carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J. Clin. Oncol. 1999; 17: 1339-1348.Keys HM, Bundy Bn, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N. Engl. J. Med. 1999; 340: 1154-1161.Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high risk cervical cancer, N. Engl. J. Med, 1999; 340: 1137-1143.Rose PG, Bundy Bn, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N. Engl. J. Med. 1999; 340:1144-1153Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a ystematic review and meta-analysis. Lancet 2001; 358: 781-786.Neoadjuvant chemotherapy for locally advanced cervical cancer: a systemic review and meta-analysis of individual patient data from 21 randomized trials. European Journal of Cancer 2003; 39: 2470-2486.Lai CH, Juang KG, Hong JH, et al. Randomized trial of surgical staging( extraperitoneal or laparoscopic) versus clinical staging in locally advanced cervical cancer. Gynecol. Oncol. 2003;89: 160-167.Haie C, Pejovic MH, Gerbaulet A, et al. Is prophylactic para-aortic irradiation worthwhile in the treatment of advanced cervical carcinoma? Results of a controlled clinical trial of the EORTC radiotherapy group. Radiother. Oncol. 1988;11:101-112.Rotman M, Pajak TF, Choi K, et al. Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIb and bulky Ib and IIa cervical carcinomas. Ten-year treatment results of RTOG 79-20, JAMA 1995; 274: 387-393.Peters WA, Lui PY, Barrett RJ, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J. Clin. Oncol. 2000; Apr; 18(8): 1606-1613.Sedlis A, Bundy BN, Rotman MZ, et al. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study. Gynecol. Oncol. 1999;73: 177-183.Bloss JD, Blessing JA, Behrens BC. et al. Randomized trial of cisplatin and ifosfamide with or without bleomycin in squamous cell carcinoma of cervix: A Gynecologic Oncology Group Study. J. Clin. Oncol. 2002; 20(7): 1832-1837.Moore DH, Blessing JA, McQuellon RP, et al. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: A Gynecologic Oncology Group Study. J. Clin. Oncol. 2004; 22(15): 3113-3119.Long III HJ, Bundy BN, Grendys Jr EC, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix. A Gynecologic Oncology Group Study. J. Clin. Oncol. 2005;23(21): 4626-4633.