NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) Cervical Cancer. Version NCCN.org. Continue

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1 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) Version NCCN.g Continue Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

2 Panel Members * Benjamin E. Greer, MD/Co-Chair Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance * Wui-Jin Koh, MD/Co-Chair Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance Nadeem R. Abu-Rustum, MD Memial Sloan-Kettering Cancer Center Sachin M. Apte, MD, MS H. Lee Moffitt Cancer Center & Research Institute Susana M. Campos, MD, MPh, MS Dana-Farber/Brigham and Women s Cancer Center John Chan, MD UCSF Helen Diller Family Comprehensive Cancer Center Kathleen R. Cho, MD University of Michigan Comprehensive Cancer Center Larry Copeland, MD The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute Marta Ann Crispens, MD Vanderbilt-Ingram Cancer Center Nefertiti DuPont, MD, MPH Roswell Park Cancer Institute Patricia J. Eifel, MD The University of Texas MD Anderson Cancer Center David K. Gaffney, MD, PhD Huntsman Cancer Institute at the University of Utah Warner K. Huh, MD University of Alabama at Birmingham Comprehensive Cancer Center Daniel S. Kapp, MD, PhD Stanfd Comprehensive Cancer Center John R. Lurain, III, MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Lainie Martin, MD Fox Chase Cancer Center Mark A. Mgan, MD Fox Chase Cancer Center Robert J. Mgan, Jr., MD City of Hope Comprehensive Cancer Center David Mutch, MD Siteman Cancer Center at Barnes- Jewish Hospital and Washington University School of Medicine Steven W. Remmenga, MD UNMC Eppley Cancer Center at The Nebraska Medical Center R. Kevin Reynolds, MD University of Michigan Comprehensive Cancer Center William Small, Jr., MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Nelson Teng, MD, PhD Stanfd Comprehensive Cancer Center Fidel A. Valea, MD Duke Comprehensive Cancer Center NCCN Miranda Hughes, PhD Nicole McMillian, MS NCCN Guidelines Panel Disclosures Continue Gynecologic oncology Medical oncology Hematology Radiotherapy/Radiation oncology Pathology * Writing committee member Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

3 Table of Contents NCCN Panel Members Summary of the Guidelines Updates Clinical Stage (CERV-1) Stage IA1, IA2 (CERV-2) Stage IB1 and Stage IIA1 (CERV-2) Stage IB2 and Stage IIA2 (CERV-2) Stage IB2, IIA2, and Stages IIB, IIIA, IIIB, IVA (CERV-4) Incidental finding of invasive cancer at simple hysterectomy (CERV-7) Surveillance (CERV-8) Local/regional recurrence (CERV-9) Distant metastases (CERV-10) Clinical Trials: The NCCN believes that the best management f any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at NCCN member institutions, click here: nccn.g/clinical_trials/physician.html NCCN Categies of Evidence and Consensus: All recommendations are Categy 2A unless otherwise specified. See NCCN Categies of Evidence and Consensus Principles of Radiation Therapy f (CERV-A) Chemotherapy Regimens f Recurrent Metastatic (CERV-B) Staging (ST-1) The NCCN Guidelines include the management of squamous cell carcinoma, adenosquamous carcinoma, and adenocarcinoma of the cervix. The NCCN Guidelines are a statement of evidence and consensus of the auths regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient s care treatment. The National Comprehensive Cancer Netwk (NCCN ) makes no representations warranties of any kind regarding their content, use application and disclaims any responsibility f their application use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Netwk. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any fm without the express written permission of NCCN Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

4 Updates Updates in Version of the NCCN Guidelines from Version include: Global Changes: The Staging tables were updated to reflect the 2009 FIGO Staging ( ST-1) and ( ST-2). The algithms were revised to reflect the new FIGO staging. Principles of Radiation Therapy is a new page that provides specific recommendations and dosing f radiation therapy throughout the NCCN Guidelines ( CERV-A). CERV-1 CERV-6 Wkup: The CBC and Imaging bullets were revised f clarity. Retroperitoneal lymph node dissection changed to Extraperitoneal (Also f CERV-7) lymph node dissection. CERV-2 CERV-7 Stage IA1; Primary Treatment: The third option changed to Stage IA1 with lymphovascular space invasion pathway: Optional Modified radical hysterectomy trachelectomy + pelvic lymph ( Stage IB2): EUA cystoscopy/proctoscopy was removed as a node dissection if lymphovascular invasion (categy 2B f node recommendation. dissection). CERV-8 Stage IA2; Primary Treatment: The second option changed from Surveillance: Patient education regarding symptoms was added. Brachytherapy + pelvic RT... to Brachytherapy ± pelvic RT... Wkup: Pelvic/abdominal/chest CT/PET scan changed to Stage IB1 and stage IIA1; Primary treatment: Radical Additional imaging as clinically indicated. trachelectomy f fertility preservation f lesions (Stage IB1)... Footnote h regarding PET-CT scan is new to the page. changed to Radical trachelectomy f tums 2 cm CERV-9 (Stage IB1)... Noncentral disease: Pelvic exenteration was removed befe CERV-3 Resection with IORT f close positive margins. Surgical Findings: Positive pelvic nodes Positive surgical Platinum-based chemotherapy changed to Chemotherapy. margin Positive parametrium changed to Positive pelvic CERV-10 nodes and/ Positive surgical margin and/ Positive Resectable: RT + concurrent chemotherapy changed to RT ± parametrium (Also f CERV-7) concurrent chemotherapy. Para-atic lymph node postive... ; Bottom pathway: Chest CT/PET scan was clarified as Chest CT PET-CT CERV-B Chemotherapy Regimens f Recurrent Metastatic Disease scan. First-line combination therapy: Cisplatin/paclitaxel changed from Systemic therapy/individualized RT changed to Systemic categy 1 to categy 2A. therapy ± individualized RT. (Also f CERV-5 and CERV-6) Second-line therapy: CERV-4 Statement changed to Agents listed are categy 2B unless Radiologic imaging only; Positive adenopathy: FNA if clinically otherwise noted. indicated changed to Consider needle biopsy. Epirubicin and liposomal doxubicin were removed. CERV-5 Pemetrexed and vinelbine changed from categy 2B to Pelvic lymph node positive/para-atic lymph... changed to categy 3. Pelvic lymph node positive and para-atic lymph node... Footnote referencing the Management of Drug Reactions (OV-C) page from the NCCN Ovarian Cancer Guidelines is new to the page. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. UPDATES

5 WORKUP CLINICAL STAGE Stage IA1 See Primary Treatment (CERV- 2) H&P CBC (including platelets) Cervical biopsy, pathologic review Cone biopsy as indicateda LFT/renal function studies Imaging (optional f stage IB1): Chest x-ray CT PET-CT scan MRI as indicated Optional ( Stage IB2): EUA cystoscopy/proctoscopyb Stage IA2 Stage IB1 Stage IIA1 Stage IB2 Stage IIA2 Stage IIB Stage IIIA, IIIB Stage IVA See Primary Treatment (CERV-2) See Primary Treatment (CERV-2 ) and (CERV-4) See Primary Treatment (CERV-4) Incidental finding of invasive cancer at simple hysterectomy See Primary Treatment (CERV-7) a See f indications f cone biopsy (MS-2). b F suspicion of bladder/bowel involvement, cystoscopy/proctoscopy with biopsy is required. All staging in guideline is based on updated 2009 FIGO staging. (See ST-1) Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CERV-1

6 Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. CLINICAL STAGE PRIMARY TREATMENT Extrafascial hysterectomy See Surveillance (CERV-8) Observe if patient desires fertility if inoperable Stage IA1 (only if cone biopsy has negative margins) Modified radical hysterectomy trachelectomy + pelvic lymph node dissection if lymphovascular invasion See Surgical Findings (CERV-3) (categy 2B f node dissection) Radical hysterectomy + pelvic lymph node dissection ± para-atic lymph node sampling See Surgical Findings (CERV-3) Stage IA2 Brachytherapy ± pelvic RT (total point A dose: Gy) c Radical trachelectomy + pelvic lymph node dissection See Surveillance (CERV-8) ± para-atic lymph node sampling Radical hysterectomy + pelvic lymph node dissection ± para-atic lymph node sampling (categy 1) See Surgical Findings (CERV-3) Stage IB1 Pelvic RT + brachytherapy (total point A dose: Gy) c and stage IIA1 Radical trachelectomy f tums 2 cm (Stage IB1) See Surveillance (CERV-8) + pelvic lymph node dissection ± para-atic lymph node sampling Pelvic RT + concurrent cisplatin-containing chemotherapyd + brachytherapy (total point A dose 85 Gy) c See Surveillance (CERV-8) (categy 1) Stage IB2 Radical hysterectomy + pelvic lymph node dissection See Surgical Findings (CERV-3) and stage IIA2 + para-atic lymph node sampling (categy 2B) ( also see CERV-4) Pelvic RT + concurrent cisplatin-containing chemotherapyd + brachytherapy (total point A dose Gy) c See Surveillance (CERV-8) + adjuvant hysterectomy (categy 3) c These doses are recommended f most patients based on summation of conventional external-beam fractionation and low-dose rate (40-70 cgy/h) brachytherapy equivalents. Modify treatment based on nmal tissue tolerance. ( See [MS-12]) d Concurrent cisplatin-based chemotherapy with RT utilizes cisplatin as a single agent cisplatin plus 5-fluouracil. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CERV-2

7 SURGICAL FINDINGS ADJUVANT TREATMENT Negative nodes Positive pelvic nodes and/ Positive surgical margin and/ Positive parametrium e Pelvic RT if combination of high-risk facts (categy 1) (ie, large primary tum, deep stromal invasion, and/ lymphovascular space invasion) ± concurrent cisplatin-based chemotherapyd (categy 2B f chemotherapy) Observe e Pelvic RT + concurrent cisplatin-containing chemotherapy (categy 1) ± vaginal brachytherapye d See Surveillance (CERV-8) Para-atic lymph node positive by surgical staging Chest CT PET-CT scan Negative f distant metastasis Positive f distant metastasis Consider biopsy of suspicious areas as indicated Negative Positive Para-atic lymph node RT + concurrent cisplatincontaining chemotherapyd + pelvic RTe ± brachytherapye Systemic therapyf ± individualized RTe e d e f Concurrent cisplatin-based chemotherapy with RT utilizes cisplatin as a single agent cisplatin plus 5-fluouracil. See Principles of Radiation Therapy f (CERV-A). See Chemotherapy Regimens f Recurrent Metastatic (CERV-B). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. See Surveillance (CERV-8) CERV-3

8 CLINICAL STAGE PRIMARY TREATMENT Radiologic imaging only Negative adenopathy e Pelvic RT + concurrent cisplatin-containing chemotherapy (categy 1) + brachytherapye d Positive adenopathy Consider needle biopsy See Imaging Results (CERV-6) Stage IB2, Stage IIA2 Stage IIB, IIIA, IIIB, IVA Surgical staging: Extraperitoneal laparoscopic lymph node dissection (categy 2B) Negative Positive Pelvic RT e + concurrent cisplatin-containing chemotherapy (categy 1) + brachytherapye See Node Status (CERV-5) d d Concurrent cisplatin-based chemotherapy with RT utilizes cisplatin as a single agent cisplatin plus 5-fluouracil. e See Principles of Radiation f (CERV-A). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. See Surveillance (CERV-8) CERV-4

9 Stage IB2, IIA2; Stage IIB, IIIA, IIIB, IVA NODE STATUS PRIMARY TREATMENT Pelvic lymph node positive and para-atic lymph node negative by surgical staging e Pelvic RT + concurrent cisplatin-containing chemotherapy d (categy 1) + brachytherapye Para-atic lymph node positive by surgical staging Further radiologic wkup as clinically indicated Negative f distant metastasis Positive f distant metastasis Consider biopsy of suspicious areas as indicated Negative Positive e Pelvic RT + para-atic lymph node RTe + concurrent cisplatin-containing chemotherapyd + brachytherapye Systemic therapyf ± individualized RTe d Concurrent cisplatin-based chemotherapy with RT utilizes cisplatin as a single agent cisplatin plus 5-fluouracil. e See Principles of Radiation Therapy f (CERV-A). fsee Chemotherapy Regimens f Recurrent Metastatic (CERV-B). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. See Surveillance (CERV-8) CERV-5

10 Stage IB2, IIA2 Stage IIB, IIIA, IIIB, IVA IMAGING RESULTS Pelvic node positive; Para-atic lymph node negative PRIMARY TREATMENT Pelvic RT + brachytherapye + concurrent cisplatincontaining chemotherapyd (categy 1) ± para-atic lymph node RTe e Extraperitoneal lymph node dissection Para-atic negative e Pelvic RT + brachytherapye + concurrent cisplatin-containing chemotherapyd (categy 1) See Surveillance (CERV-8) Positive adenopathy by CT, MRI and/ PET Pelvic node positive; Paraatic lymph node positive Consider extraperitoneal lymph node dissection Para-atic positive Extended-field RTe + brachytherapye + concurrent cisplatin-containing chemotherapyd Distant metastases; with biopsy confirmation as clinically indicated Systemic therapyf ± individualized RTe d Concurrent cisplatin-based chemotherapy with RT utilizes cisplatin as a single agent cisplatin plus 5-fluouracil. e See Principles of Radiation Therapy f (CERV-A). fsee Chemotherapy Regimens f Recurrent Metastatic (CERV-B). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. See Surveillance (CERV-8) CERV-6

11 INCIDENTAL FINDING OF INVASIVE CANCER AT SIMPLE HYSTERECTOMY PRIMARY TREATMENT Stage IA1 Stage IA1 with lymphovascular space invasion Stage IA2 Pathologic review H&P CBC (including platelets) LFT/renal function studies Imaging (optional f stage IB1): Chest x-ray CT PET-CT scan MRI as indicated No lymphovascular space invasion Negative margins; negative imaging Positive margins g, gross residual disease, positive imaging d Concurrent cisplatin-based chemotherapy with RT utilizes cisplatin as a single agent cisplatin plus 5-fluouracil. esee Principles of Radiation Therapy f (CERV-A). g Invasive cancer at surgical margin. Pelvic RTe + brachytherapy ± concurrent cisplatincontaining chemotherapyd Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Complete parametrectomy + upper vaginectomy + pelvic lymph node dissection ± para-atic lymph node sampling e Imaging negative f nodal disease Imaging positive f nodal disease See Surveillance CERV-8 Negative nodes Positive nodes and/ Positive surgical margin and/ Positive parametrium Consider surgical debulking of grossly enlarged nodes Observe Optional pelvic RTe ± vaginal brachytherapy if large primary tum, deep stromal invasion and/ lymphovascular space invasion Pelvic RTe (para-atic lymph node RT if para-atic lymph node positive) + concurrent cisplatincontaining chemotherapyd ± individualized brachytherapye (if positive vaginal margin) See Surveillance (CERV-8) e Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CERV-7

12 SURVEILLANCE WORKUP Interval H&P Cervical/vaginal cytology every 3-6 mo f 2 y, then every 6 mo f 3-5 yrs, then annually Chest x-ray annually (optional) CBC, BUN, creatinine every 6 mo (optional) PET-CT scan as clinically indicatedh Recommend use of vaginal dilat after RT Patient education regarding symptoms Persistent recurrent disease Additional imaging as clinically indicated Surgical explation in selected cases See Therapy f Relapse (Local/regional recurrence) (CERV-9) See Therapy f Relapse (Distant metastases) (CERV-10) h PET-CT scan may be useful in detecting isolated recurrences persistent disease that is amenable to potentially curative salvage therapy. (See [MS-7]) Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CERV-8

13 THERAPY FOR RELAPSE Local/ regional recurrence No pri RT failure outside of previously treated field Pri RT Central disease Consider surgical resection, if feasible Tum-directed RT + platinum-based chemotherapyd ± brachytherapye Pelvic exenteration ± intraoperative RT (IORT) In carefully selected patients with small (< 2 cm) lesions e Recurrence Recurrence Radical hysterectomy Brachytherapy e Chemotherapyf Best supptive care (See NCCN Palliative Care Guidelines) Clinical trial Noncentral disease Resection with IORT f close positive margins Tum-directed RT e ± chemotherapyd,f Chemotherapyf Best supptive care (See NCCN Palliative Care Guidelines) Clinical trial d Concurrent cisplatin-based chemotherapy with RT utilizes cisplatin as a single agent cisplatin plus 5-fluouracil. esee Principles of Radiation Therapy f (CERV-A). fsee Chemotherapy Regimens f Recurrent Metastatic (CERV-B). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CERV-9

14 THERAPY FOR RELAPSE Multiple sites Unresectable Chemotherapyf Best supptive care (See NCCN Palliative Care Guidelines) Distant metastases Resectable Consider resection ± IORT RTe± concurrent chemotherapy Chemotherapyf d See Surveillance (CERV-8) d Concurrent cisplatin-based chemotherapy with RT utilizes cisplatin as a single agent cisplatin plus 5-fluouracil. esee Principles of Radiation Therapy f (CERV-A). fsee Chemotherapy Regimens f Recurrent Metastatic (CERV-B). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CERV-10

15 PRINCIPLES OF RADIATION THERAPY FOR CERVICAL CANCER External-Beam Radiation Therapy (EBRT) The use of computed tomography (CT) based treatment planning and confmal blocking is considered standard of care f EBRT. MRI is the best imaging modality f determining soft tissue and parametrial involvement in patients with advanced tums. In patients who are not surgically staged, PET imaging is useful to help define the nodal volume of coverage. The volume of EBRT should cover the gross disease (if present), parametria, uterosacral ligaments, sufficient vaginal margin from the gross disease (at least 3 cm), presacral nodes, and other nodal volumes at risk. F patients with negative nodes on surgical radiologic imaging, the radiation volume should include the entirety of the external iliac, internal iliac, and obturat nodal basins. F patients deemed at higher risk of lymph node involvement (eg, bulkier tums, suspected confirmed nodes confined to the low true pelvis), the radiation volume should be increased to cover the common iliacs as well. In patients with documented common iliac and/ para-atic nodal involvement, extended-field pelvic and para-atic radiotherapy would be required, up to the level of the renal vessels ( even me cephalad as directed by involved nodal distribution). Coverage of microscopic nodal disease requires an EBRT dose of approximately 45 Gy (in conventional fractionation of Gy daily), and highly confmal boosts of an additional Gy may be considered f limited volumes of gross unresected adenopathy. F the majity of patients who receive EBRT f cervical cancer, concurrent cisplatin-based chemotherapy (either cisplatin alone, cisplatin + 5-fluouracil) is given during the time of EBRT. Brachytherapy Brachytherapy is a critical component of therapy f all patients with intact cervical cancer. This is usually perfmed using an intracavitary approach, with an intrauterine tandem and vaginal colpostats. Depending on the patient and tum anatomy, the vaginal component of brachytherapy in patients with intact cervical cancer may be delivered using ovoids, ring, cylinder (combined with the intrauterine tandem). When combined with EBRT, brachytherapy is often initiated towards the latter part of treatment, when sufficient primary tum regression has been noted to permit satisfacty brachytherapy apparatus geometry. In highly selected very early disease (ie, stage IA2), brachytherapy alone, without external-beam radiation, may be an option. In rare cases, patients whose tum geometry renders intracavitary brachytherapy infeasible may be best treated using an interstitial approach; however, such interstitial brachytherapy should only be perfmed by individuals and at institutions with appropriate experience and expertise. In selected post-hysterectomy patients (especially those with positive vaginal mucosal surgical margins), vaginal cylinder brachytherapy may be used as a boost to EBRT. Continued Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CERV-A 1 of 4

16 PRINCIPLES OF RADIATION THERAPY FOR CERVICAL CANCER Radiation Dosing Considerations The most common histical dosing parameters f brachytherapy utilize a system that includes specifying dose at point A, and that incpates specific guidelines f 'radioactive source loading and distribution of activity' within the uterus and vagina, based on anatomic considerations. Doses are also calculated at standardized point B and bladder and rectal points. Current effts at '3-D' image-guided brachytherapy seek to optimize implant dose coverage of tum, while potentially reducing dose to adjacent bladder, rectum, and bowel structures. 1 Nonetheless, the weight of experience and tum control results, and the majity of continuing clinical practice, have been based on the point A dosing system. 2 Attempts to improve dosing with image-guided brachytherapy should take care not to underdose tums relative to the point A system dose recommendations. The point A dose recommendations provided in the NCCN GuidelinesTM are based on traditional, and widely validated, dose fractionation and brachytherapy at low dose rates. In these provided dose recommendations, f EBRT, the dose is delivered at Gy per daily fraction. F brachytherapy, the dose at point A assumes a low-dose rate (LDR) delivery of cgy/h. Clinicians using high-dose rate (HDR) brachytherapy would depend on the linear-quadratic model equation to convert nominal HDR dose to point A to a biologically equivalent LDR dose to point A ( ). Multiple brachytherapy schemes have been used, when combined with EBRT. However, one of the me common HDR approaches is 5 insertions with tandem and colpostats, each delivering 6 Gy nominal dose to point A. This results in a nominal HDR point A dose of 30 Gy in 5 fractions, which is generally accepted to be the equivalent to 40 Gy to point A (tum surrogate dose) using LDR brachytherapy. Definitive Radiation Therapy f Intact In patients with intact cervical cancer (ie, those who do not have surgery), the primary tum and regional lymphatics at risk are typically treated with definitive EBRT to a dose of approximately 45 Gy (40-50 Gy). The volume of the EBRT would depend on the nodal status as determined surgically radiographically (as previously described). The primary cervical tum is then boosted, using brachytherapy, with an additional Gy to point A (in LDR equivalent dose), f a total point A dose (as recommended in the guidelines) of 80 Gy (small volume cervical tums) to 85 Gy greater (larger volume cervical tums). Grossly involved unresected nodes may be evaluated f boosting with an additional Gy of highly confmal (and reduced volume) EBRT. With higher doses, especially of EBRT, care must be taken to exclude, to severely limit, the volume of nmal tissue included in the high-dose region(s) ( see ). Continued Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CERV-A 2 of 4

17 PRINCIPLES OF RADIATION THERAPY FOR CERVICAL CANCER Post-Hysterectomy Adjuvant Radiation Therapy Following primary hysterectomy, the presence of one me pathologic risk facts may warrant the use of adjuvant radiotherapy. At a minimum, the following should be covered: upper 3-4 cm of the vaginal cuff, the parametria, and immediately adjacent nodal basins (such as the external and internal iliacs). Where there is documented nodal metastasis, the superi bder of the radiation field should be appropriately increased (as previously described). A dose of Gy in standard fractionation is generally recommended. Grossly involved unresected nodes may be evaluated f boosting with an additional Gy of highly confmal (and reduced volume) EBRT. With higher doses, especially of EBRT, care must be taken to exclude, to severely limit, the volume of nmal tissue included in the high-dose region(s) ( see ). Intraoperative Radiation Therapy (IORT) IORT is a specialized technique that delivers a single, highly focused dose of radiation to a tum bed at risk, isolated unresectable residual, during an open surgical procedure. 3 It is particularly useful in patients with recurrent disease within a previously radiated volume. During IORT, overlying nmal tissue (such as bowel other viscera) can be manually displaced from the region at risk. IORT is typically delivered with electrons using pre-fmed applicats of variable sizes (matched to the surgically defined region at risk), which further constrain the area and depth of radiation exposure to avoid surrounding nmal structures. Continued Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CERV-A 3 of 4

18 PRINCIPLES OF RADIATION THERAPY FOR CERVICAL CANCER (REFERENCES) 1Pötter R, Haie-Meder C, Van Limbergen E, et al. Recommendations from gynaecological (GYN) GEC ESTRO wking group (II): concepts and terms in 3D imagebased treatment planning in cervix cancer brachytherapy-3d dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78(1): Epub 2006 Jan 5. 2Viswanathan AN, Erickson BA. Three-dimensional imaging in gynecologic brachytherapy: a survey of the American Brachytherapy Society. Int J Radiat Oncol Biol Phys 2010;76(1): del Carmen MG, McIntyre JF, Goodman A. The role of intraoperative radiation therapy (IORT) in the treatment of locally advanced gynecologic malignancies. Oncologist 2000;5(1): Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CERV-A 4 of 4

19 CHEMOTHERAPY REGIMENS FOR RECURRENT OR METASTATIC CERVICAL CANCER (Strongly consider clinical trial) First-line combination therapy Cisplatin/paclitaxel1,2 Carboplatin/paclitaxel3 Cisplatin/topotecan4 Cisplatin/gemcitabine (categy 2B) 5 Possible first-line single agent therapy Cisplatin (preferred as a single agent) Carboplatin6 Paclitaxel 7 2 Second-line therapy (Agents listed are categy 2B unless otherwise noted) Bevacizumab Docetaxel 5-FU (5-fluouracil) Gemcitabine Ifosfamide Irinotecan Mitomycin Topotecan Pemetrexed (categy 3) Vinelbine (categy 3) Continued Cisplatin, carboplatin, docetaxel, and paclitaxel may cause drug reactions References f second-line therapy are provided in the. ( See NCCN Ovarian Cancer Guidelines--Management of Drug Reactions [OV-C]) Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CERV-B 1 of 2

20 CHEMOTHERAPY REGIMENS FOR RECURRENT OR METASTATIC CERVICAL CANCER (References) 1 Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, persistent cervical carcinoma: A Gynecologic Oncology Group Study. J Clin Oncol 2009; 27: Moe DH, Blessing JA, McQuellon RP, et al. Phase III study of cisplatin with without paclitaxel in stage IVB, recurrent, persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol. 2004;22: Moe KN, Herzog TJ, Lewin S, et al. A comparison of cisplatin/paclitaxel and carboplatin/paclitaxel in stage IVB, recurrent persistent cervical cancer. Gynecol Oncol 2007;105: Long HJ, 3rd, Bundy BN, Grendys EC, Jr., et al. Randomized phase III trial of cisplatin with without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol. 2005;23: Brewer CA, Blessing JA, Nagourney RA, et al. Cisplatin plus gemcitabine in previously treated squamous cell carcinoma of the cervix. Gynecol Oncol 2006;100: Weiss GR, Green S, Hannigan EV, et al. A phase II trial of carboplatin f recurrent metastatic squamous carcinoma of the uterine cervix: a Southwest Oncology Group study. Gynecol Oncol. 1990;39: Kudelka AP, Winn R, Edwards CL, et al. An update of a phase II study of paclitaxel in advanced recurrent squamous cell cancer of the cervix. Anticancer Drugs 1997;8: Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CERV-B 2 of 2

21 Staging Table 1 AJCC Tum-Node-Metastases (TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems f Carcinoma of the Uterine Cervix TNM FIGO Surgical-Pathologic Findings Categies Stages TX Primary tum cannot be assessed T0 No evidence of primary tum Tis* Carcinoma in situ (preinvasive carcinoma) T1 I Cervical carcinoma confined to cervix (extension to cpus should be disregarded) T1a** IA Invasive carcinoma diagnosed only by microscopy. Stromal invasion with a maximum depth of 5.0 mm measured from the base of the epithelium and a hizontal spread of 7.0 mm less. Vascular space involvement, venous lymphatic, does not affect classification T1a1 IA1 Measured stromal invasion 3.0 mm less in depth and 7.0 mm less in hizontal spread T1a2 IA2 Measured stromal invasion me than 3.0mm and not me than 5.0 mm with a hizontal spread 7.0 mm less T1b IB Clinically visible lesion confined to the cervix microscopic lesion greater than T1a/IA2# T1b1 IB1 Clinically visible lesion 4.0 cm less in greatest dimension T1b2 IB2 Clinically visible lesion me than 4.0 cm in greatest dimension T2 II Cervical carcinoma invades beyond uterus but not to pelvic wall to lower third of vagina Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. TNM FIGO Surgical-Pathologic Findings Categies Stages T2a IIA Tum without parametrial invasion T2a1 IIA1 Clinically visible lesion 4.0 cm less in greatest dimension T2a2 IIA2 Clinically visible lesion me than 4.0 cm in greatest dimension T2b IIB Tum with parametrial invasion T3 III Tum extends to pelvic wall and/ involves lower third of vagina and/ causes hydronephrosis nonfunctioning kidney## T3a IIIA Tum involves lower third of vagina, no extension to pelvic wall T3b IIIB Tum extends to pelvic wall and/ causes hydronephrosis nonfunctioning kidney T4 IVA Tum invades mucosa of bladder rectum, and/ extends beyond true pelvis (bullous edema is not sufficient to classify a tum as T4) *Note: FIGO no longer includes Stage 0 (Tis). **Note: All macroscopically visible lesions even with superficial invasion are T1b/IB. # All macroscopically visible lesions even with superficial invasion are allotted to stage IB carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.00 mm and a hizontal extension of not >7.00 mm. Depth of invasion should not be > 5.00mm taken from the base of the epithelium of the iginal tissue superficial glandular. The depth of invasion should always be repted in mm, even in those cases with early (minimal) stromal invasion (~1 mm). The involvement of vascular/lymphatic spaces should not change the stage allotment. ## On rectal examination, there is no cancer-free space between the tum and the pelvic wall. All cases with hydronephrosis non-functioning kidney are included, unless they are known to be due to another cause. Continued... Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (F complete infmation and data suppting the staging tables, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. and Reprinted from: Pecelli S. Revised FIGO staging f carcinoma of the vulva, cervix and endometrium. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet 2009;105: Copyright 2009, with permission from International Federation of Gynecology and Obstetrics. ST-1

22 Staging- Staging Table 1-Continued AJCC Tum-Node-Metastases (TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems f Carcinoma of the Uterine Cervix Regional Lymph Nodes (N) TNM FIGO Categies Stages NX N0 N1 Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis Distant Metastasis (M) TNM FIGO Categies Stages M0 No distant metastasis M1 IVB Distant metastasis (including peritoneal spread, involvement of supraclavicular, mediastinal, paraatic lymph nodes, lung, liver, bone) Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (F complete infmation and data suppting the staging tables, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. and Reprinted from: Pecelli S. Revised FIGO staging f carcinoma of the vulva, cervix and endometrium. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet 2009;105: Copyright 2009, with permission from International Federation of Gynecology and Obstetrics. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ST-2

23 NCCN Categies of Evidence and Consensus Categy 1: The recommendation is based on high-level evidence (e.g. randomized controlled trials) and there is unifm NCCN consensus. Categy 2A: The recommendation is based on lower-level evidence and there is unifm NCCN consensus. Categy 2B: The recommendation is based on lower-level evidence and there is nonunifm NCCN consensus (but no maj disagreement). Categy 3: The recommendation is based on any level of evidence but reflects maj disagreement. All recommendations are categy 2A unless otherwise noted. Overview An estimated 12,200 new cases of cervical cancer will be diagnosed in the United States in the year 2010; 4200 deaths will result from the disease. 1 Cervical cancer rates are decreasing among women in the United States, although incidence remains high among Hispanic/Latino, Black, and Asian women. 2-5 However, cervical cancer is a maj wld health problem f women. The global yearly incidence of cervical cancer f 2002 was 493,200; the annual death rate was 273,500. It is the third most common cancer in women wldwide; 6, 7 78% of cases occur in developing countries, where cervical cancer is the second most frequent cause of cancer death in women. Persistent human papillomavirus (HPV) infection is regarded as the most imptant fact contributing to the development of cervical cancer. There appears to be a relationship between the incidence of cervical cancer and the prevalence of HPV in the population. The prevalence of chronic HPV in countries with a high incidence of cervical cancer is about 10% to 20%, whereas the prevalence in low-incidence countries is 5% to 10%. 6 Immunization against HPV prevents infection with certain types of HPV and, thus, is expected to prevent specific HPV cancer in women (see NCCN Screening Guidelines) Other epidemiologic risk facts associated with cervical cancer are a histy of smoking, parity, contraceptive use, early age of onset of coitus, larger number of sexual partners, histy of sexually transmitted disease, and chronic immunosuppression. 13 Squamous cell carcinomas account f about 80% of all cervical cancers and adenocarcinoma f about 20%. In developed countries, the substantial decline in incidence and mtality of squamous cell carcinoma of the cervix is thought to be a result of effective screening, 2, 3, 14, 15 although there are racial, ethnic, and geographic disparities. However, adenocarcinoma of the cervix has increased over the last 3 decades, probably because cervical cytologic screening methods are less effective f adenocarcinoma Screening methods using HPV testing may increase detection of adenocarcinoma. Vaccination with HPV vaccines may also decrease the incidence of both squamous cell 18, 20 carcinoma and adenocarcinoma. By definition, the NCCN practice guidelines cannot incpate all possible clinical variations and are not intended to replace good clinical judgment individualization of treatments. Many exceptions to the rule were discussed among the members of the cervical cancer panel during the process of developing these guidelines. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-1

24 Diagnosis and Wkup These NCCN guidelines discuss squamous cell carcinoma, adenosquamous carcinoma, and adenocarcinoma of the cervix. Neuroendocrine carcinoma, small cell tums, glassy-cell carcinomas, sarcomas, and other histologic types are not within the scope of these guidelines. Currently, the International Federation of Gynecology and Obstetrics (FIGO) evaluation procedures f staging are limited to colposcopy, biopsy, conization of the cervix, cystoscopy, and proctosigmoidoscopy. Me complex radiologic and surgical staging procedures are not addressed in the FIGO classification. In the United States, however, computed tomography (CT), magnetic resonance imaging (MRI), combined positron emission tomography (PET)-CT, and surgical staging are often used to guide treatment options and design The earliest stages of cervical carcinoma may be asymptomatic associated with a watery vaginal discharge and postcoital bleeding intermittent spotting. These early symptoms frequently are unrecognized by the patient. Because of the accessibility of the uterine cervix, cervical cytology Papanicolaou (Pap) smears and cervical biopsies can usually result in an accurate diagnosis (see NCCN Screening Guidelines). Cone biopsy (i.e., conization) is recommended if the cervical biopsy is inadequate to define invasiveness if accurate assessment of microinvasive disease is required. However, cervical cytologic screening methods are less useful f diagnosing adenocarcinoma, because adenocarcinoma in situ affects areas of the cervix that are harder to sample (i.e., endocervical 5, 19 canal). Wkup f these patients with suspicious symptoms includes histy and physical examination, complete blood count (including platelets), and liver and renal function tests. Radiologic imaging includes chest x-ray, CT combined PET-CT, and MRI as indicated (e.g., to rule out disease high in the endocervix); however, imaging is optional f patients with stage IB1 smaller tums (see CERV-1). Cystoscopy and proctoscopy should be reserved f patients in whom there is clinical concern f bladder rectal extension. Panel members discussed whether laparoscopic and robotic approaches should be included as part of these NCCN guidelines in both staging and treatment. These techniques are being used me frequently, but long-term outcome data are not available yet. Laparoscopic staging, lymphadenectomies, and radical hysterectomies can be perfmed satisfactily and are used routinely in selected patients in several member institutions Data from studies overseas suggest that recurrence rates are low f laparoscopic radical hysterectomy after 3-6 years of follow-up. 27, 28 Robotic radical hysterectomy (which is another minimally invasive surgical technique) is currently being done f patients with early cervical cancer. Potential advantages associated with laparoscopic and robotic approaches include decreased hospital stay and me rapid patient recovery Staging Because of the variability of the availability and wldwide use of noninvasive radiographic imaging, the FIGO system limits the imaging to chest radiography, intravenous pyelography (IVP), and barium enema. The staging of carcinoma of the cervix remains largely a clinical evaluation. Although surgical staging is me accurate than clinical staging, surgical staging often cannot be used in low resource countries. 22, 32, 33 The guidelines panel currently uses the 2009 FIGO definitions and staging system (see Table 1). 32, 34 This staging system from FIGO has been approved by the American Joint Committee on Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-2

25 Cancer (AJCC). 35 With the new staging, stage IIA is now subdivided into stage IIA1 (tum size 4 cm less) and stage IIA2 (tum size me than 4 cm), which is the only change from the previous 1994 FIGO staging system. It is imptant to note that lymphatic vascular space involvement (LVSI) does not alter the FIGO classification. 32 FIGO did not include vascular space involvement, because pathologists do not always agree on whether LVSI is present in tissue samples. Some panel members believe that the presence of frank LVSI should exclude the lesion from the treatment schema f stage IA1 and that these patients should be treated using stage 1B1 guidelines. The use of MRI, CT, combined PET-CT scans may aid in treatment 22, 33, 36, 37 planning but is not accepted f fmalized staging purposes. In addition, FIGO has always maintained that staging is intended f comparison purposes only and not as a guide f therapy. As a result, the panel uses the FIGO definitions as the stratification system f these guidelines, although the findings on imaging studies (i.e., CT and MRI) are used to guide treatment options and design. MRI is useful to rule out disease high in the endocervix. Primary Treatment The primary treatment of early stage cervical cancer is either surgery radiation therapy (RT). Surgery is typically reserved f lower-stage disease and smaller lesions, such as stage IA, IB1, and selected IIA1. The NCCN panel agrees that concurrent chemadiation is the primary treatment of choice f stages IB2-IVA disease based on the results of 5 randomized clinical trials (see Table 2). Chemadiation can also be used f patients who are not candidates f hysterectomy. Although there are few studies assessing treatment specifically f adenocarcinoma, a recent analysis suggests that they can be effectively treated in a similar manner to squamous cell carcinomas. 38,39 Clinical Trials and Basis f Treatment Selection A randomized Italian study compared RT alone versus radical hysterectomy and lymph node dissection. 40 This study used adjuvant RT after surgery f women with surgical stage pt2b (which cresponds to FIGO stage IIB) me extensive disease, less than 3 mm of uninvolved cervical stroma, and cut-through positive nodes. Identical outcomes were noted f patients treated with radiation versus surgery, with ( without) postoperative radiation, but higher complication rates were noted f the combined modality approach. This study has been criticized by surgeons f its broad use of postoperative RT in the surgery arm and the high complication rate. Concurrent chemadiation, using cisplatin-based chemotherapy (either cisplatin alone cisplatin/5-fluouracil [5-FU]), is the treatment of choice f stages IB2, II, III, and IVA disease based on the results of 5 randomized clinical trials (see Table 2) These 5 trials have shown that the use of concurrent chemadiation results in a 30% to 50% decrease in the risk of death compared to RT alone. Although the optimal concurrent chemotherapy regimen to use with RT requires further investigation, these 5 trials clearly established a role f concurrent cisplatin-based chemadiation. Based on this data, the National Cancer Institute issued an alert stating that strong consideration should be given to using chemadiation instead of RT alone f invasive cervical cancer ( Long-term follow-up of 3 of these trials has confirmed that concurrent cisplatin-based chemadiation improves progression-free and overall survival when compared with RT with without hydroxyurea A recent metaanalysis repted that chemadiotherapy leads to a 6% improvement Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-3

26 in 5-year survival (hazard ratio [HR] = 0.81, P<.001). 50 A large population-based registry analysis in Canada (n=4069) confirmed that chemadiotherapy improved outcomes when compared with radiotherapy alone. 51 Although chemadiation is tolerated, acute and long-term side effects have been repted. 50, 52, 53 Some oncologists feel that concurrent single-agent cisplatin chemadiation is preferred to cisplatin plus 5-FU chemadiation, because the latter may be me toxic. 54 Concurrent carboplatin non-platinum chemadiation regimens are options f patients who may not tolerate cisplatin-containing chemadiation. 50,55-59 Note that when concurrent chemadiation is used, the chemotherapy is typically given when the external-beam pelvic radiation is administered. 54 The NCCN panel believes that using systemic consolidation (i.e., adding chemotherapy after chemadiation) should only be used in clinical trials (e.g., RTOG 50, 60, ). Early Stage Disease After careful clinical evaluation and staging, the primary treatment of early stage cervical cancer is either surgery RT. The treatment schema is stratified using the FIGO staging system (see Table 1). Stage IA1 Disease Extrafascial (i.e., simple) hysterectomy is commonly recommended f patients with clinical stage IA1 disease; another option is modified radical hysterectomy with pelvic lymph node dissection if lymphovascular space invasion is present (categy 2B f node dissection only). However, if the patient is medically inoperable if fertility is desired, patients with negative margins from cone biopsy could undergo observation. 62, 63 F patients who desire fertility preservation, trachelectomy and pelvic lymph node dissection can be considered with ( without) para-atic lymph node sampling f stage IA cervical cancer (see CERV-2) Stage IA2 Disease Stage IA2 tums can be treated with radical hysterectomy radical trachelectomy and pelvic lymph node dissection with ( without) paraatic lymph node sampling. Para-atic node dissection is indicated f patients with known suspected pelvic nodal disease. Brachytherapy with ( without) pelvic radiation (total point A dose: Gy) is another treatment option f stage IA2 disease. These doses are recommended f most patients based on summation of conventional external-beam fractionation and low-dose-rate (40-70 cgy/h) brachytherapy equivalents. Treatment should be modified based on nmal tissue tolerance on biologic equivalence calculations when using high dose rate brachytherapy (see also Radiation Therapy section on MS-10). Stage IB and IIA Disease Depending on their stage and disease bulk, patients with stage IB IIA tums can be treated with surgery, RT, concurrent chemadiation. A combined PET-CT scan can be done to rule out extrapelvic disease pri to deciding how to treat these patients. The surgical option includes radical hysterectomy plus bilateral pelvic lymph node dissection with without para-atic lymph node sampling. 40 Paraatic node dissection is indicated f patients with larger tums and suspected known pelvic nodal disease. Some panel members feel that a pelvic lymph node dissection should be done first and if negative, then the radical hysterectomy should be done. If the lymph nodes are positive, then the hysterectomy should be abandoned; these patients should receive chemadiation. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-4

27 F patients who desire fertility preservation, radical trachelectomy and pelvic lymph node dissection with ( without) para-atic lymph node sampling can be considered f stage IB1 tums 2 cm less (see CERV-2) In one study, oncologic outcomes were similar after 4 years when comparing radical trachelectomy with radical hysterectomy f patients with stage 1B1 cervical carcinoma. 68 A study found that among women attempting to conceive after radical trachelectomy f early stage cervical cancer, the 5-year cumulative pregnancy rate was 52.8%; the cancer recurrence rate was low, but the miscarriage rate is higher. 69 F young (< 45 years) premenopausal women with early stage squamous cell carcinoma who opt f ovarian preservation (i.e., 70, 71 hysterectomy only), the rate of ovarian metastases is low. Recent data have suggested that sentinel lymph node biopsy may be useful f decreasing the need f pelvic lymphadenectomy in patients with early stage cervical cancer, but panel members believe the technique is not yet sufficiently validated However, this is an interesting area f further research F patients with stage IB IIA tums (including those who are not candidates f hysterectomy), another option is combined pelvic radiotherapy and brachytherapy with without concurrent cisplatincontaining chemotherapy (see CERV-2). Although concurrent chemadiation has been proven effective in the definitive treatment of me advanced stage disease, this approach has not been specifically studied in patients with stage IB1 IIA1 disease. Careful consideration of the risk/benefit ratio should be undertaken in these patients with smaller tums. F patients with clinical stage IB2 IIA2 tums who are treated with definitive radiation, concurrent cisplatin-containing chemotherapy has been shown to significantly improve patient survival. 41, 42 F stage IB2 IIA2 tums, the panel disagreed (categy 3) about recommending adjuvant hysterectomy f patients undergoing primary chemadiation. 41 Advanced Disease This categy has traditionally included patients with stage IIB-IVA disease (i.e., locally advanced disease). However, many oncologists now include patients with IB2 and IIA2 disease in the advanced disease categy. F patients with me advanced tums who are undergoing primary chemadiation, the volume of RT is critical and is guided by assessment of nodal involvement in the pelvic and para-atic nodes. Radiologic imaging studies (including PET-CT) are recommended f stage IB2 greater disease. MRI is useful to rule out disease high in the endocervix. However, needle biopsy can be considered f questionable imaging findings. Surgical staging (i.e., extraperitoneal laparoscopic lymph node dissection) is also an option (categy 2B) f these patients. Surgical staging may also detect microscopic nodal disease that is not discernable with radiologic imaging. 79 F patients without nodal disease with disease limited to the pelvis only by surgical staging, treatment consists of pelvic RT with concurrent 42, 44-46, 54 cisplatin-based chemotherapy and brachytherapy (categy 1). However, f patients with positive para-atic and pelvic lymph nodes by imaging, extraperitoneal lymph node dissection should be considered followed by extended-field RT, concurrent cisplatincontaining chemotherapy, and brachytherapy (see CERV-6). Patients with positive para-atic lymph nodes who are positive f distant metastases are treated with systemic chemotherapy (see CERV-B) and individualized RT. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-5

28 Metastatic Disease F patients who present with distant metastatic disease (i.e., stage IVB), primary treatment is often cisplatin-based chemotherapy (see Systemic Therapy f Metastatic Disease [MS-8]). In these situations, individualized RT may be considered f control of pelvic disease and all other symptoms. Adjuvant Treatment Adjuvant treatment is indicated after radical hysterectomy depending on surgical findings and disease stage. Observation is appropriate f patients with stage IA2, IB1, IIA1 disease who have negative nodes and no risk facts after radical hysterectomy. However, adjuvant treatment is indicated after radical hysterectomy if pathologic risk facts are discovered. F patients with stage IA2, IB1, IIA1 disease who have negative lymph nodes after surgery but have large primary tum size, deep stromal invasion, and/ LVSI, pelvic radiation is recommended (categy 1) with ( without) concurrent cisplatin-based chemotherapy (categy 2B f chemotherapy) Adjuvant pelvic RT alone versus no further therapy was tested in a randomized trial (Gynecologic Oncology Group [GOG] 92) of selected patients with node-negative stage IB carcinoma of the cervix after hysterectomy and pelvic lymphadenectomy. 83 Patients were eligible f this trial after radical hysterectomy and pelvic lymphadenectomy if they had at least 2 of the following risk facts: (1) greater than one-third stromal invasion; (2) capillary lymphatic space involvement; (3) cervical tum diameters me than 4 cm. Patients with positive lymph nodes involved surgical margins were excluded. At 2 years, the recurrence-free rates were 88% f the RT group versus 79% f the no further treatment group. After long-term follow-up (12 years), an updated analysis confirmed that pelvic RT increased progression-free survival; there was also a clear trend towards improved overall survival (P=.07). 84 Patients with positive pelvic nodes, positive surgical margin, and/ positive parametrium should be treated with postoperative pelvic radiation with concurrent cisplatin-containing chemotherapy (categy 1) 43 with ( without) vaginal brachytherapy (see CERV-3). Vaginal brachytherapy may be a useful boost f those with positive vaginal mucosal margins. The addition of concurrent chemadiation significantly improves overall survival f high-risk patients with early stage disease (those with positive lymph nodes, parametrial extension, and/ positive margins) who undergo radical hysterectomy and pelvic lymphadenectomy. 43 The Intergroup Trial 0107 showed a statistically significant benefit of adjuvant pelvic radiation with concurrent cisplatin and 5-FU in the treatment of patients with stage IA2, IB, IIA disease who had positive lymph nodes, positive margins, and/ microscopic parametrial involvement found at surgery. 43 If para-atic lymph nodes are found positive during surgical staging, patients must undergo further screening with chest CT combined PET-CT scan. In women who are positive f distant metastases, biopsy of suspicious areas should be considered as indicated (see CERV-3). F patients without distant metastases, recommended treatment is extended-field RT (including pelvis and para-atic lymph nodes), concurrent cisplatin-based chemotherapy with ( without) brachytherapy. F patients with distant metastases, recommended treatment is systemic chemotherapy (see CERV-B) and individualized radiotherapy. Surveillance Because no definitive study unifm agreement exists on the best method f post-treatment surveillance f cervical cancer, the panel Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-6

29 combined the practice patterns of member institutions and issued consensus recommendations. Patient follow-up includes interval histy and physical examination, with cervical/vaginal cytology every 3-6 months f 2 years, every 6 months f another 3-5 years, and then annually (see CERV-8). Some clinicians have suggested that rigous cytology follow-up is not warranted because of studies stating that Pap smears did not detect recurrences in patients with stage I-II cervical cancer who were asymptomatic after treatment. 85, 86 It is imptant to emphasize good clinical evaluation and a high index of suspicion, because the detection rate of recurrent cervical cancer is low using cervical and vaginal cytology alone. 87 Patient education regarding symptoms suggestive of recurrence is appropriate. In patients at high risk f local-regional (central para-atic) failure, a combined PET-CT scan may be useful f detecting asymptomatic disease that is potentially curable Annual chest radiographs are optional. 87, 91 Many other tests remain optional based on clinical indications, such as semiannual complete blood counts, blood urea nitrogen, and serum creatinine determinations (see CERV-8). Patients with persistent recurrent disease need to be evaluated using additional imaging studies as clinically indicated and surgical explation in selected cases followed by therapy f relapse (see next section). 92 Vaginal dilats are recommended after pelvic RT, because patients who receive RT are prone to vaginal stenosis, which can impair sexual function. Women can use vaginal dilats to prevent treat vaginal stenosis. Dilat use can start 2-4 weeks after RT is completed and can be done indefinitely ( Cervical cancer survivs are at risk f second cancers. 93 Data suggest that patients who receive radiation therapy f pelvic cancers are at risk f radiation-induced second cancers, especially at radiated sites near the cervix (e.g., colon, rectum/anus, urinary bladder); therefe, careful 94, 95 surveillance is appropriate f these patients. Therapy f Relapse Local/Regional Therapy Patients with a localized recurrence of cervical cancer after initial treatment should be evaluated to determine whether radiotherapy surgery can be utilized f relapse. Long-term disease-free survival rates of approximately 40% have been repted in some situations. 96 F patients who experience local/regional recurrences who have not previously had RT who experience recurrences outside of the previously treated RT field, therapy f relapse includes tum-directed RT and platinum-based chemotherapy with ( without) brachytherapy; surgical resection can be considered if feasible (see CERV-9). Typically the chemadiation f recurrence uses cisplatin as a single agent 97, 98 cisplatin plus 5-FU. Patients with central pelvic recurrent disease after RT should be evaluated f pelvic exenteration, with ( without) intraoperative RT (IORT) Surgical mtality is generally 5% lower, with survival rates approaching 50%. 101 Concomitant measures with such radical procedures include adequate rehabilitation programs dealing with the psychosocial and psychosexual consequences of the operation as well as reconstructive procedures. 100, Although exenteration is the common surgical approach in post-radiation patients, in carefully selected patients with small central lesions (less than 2 cm), options may include radical hysterectomy brachytherapy. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-7

30 F patients with noncentral recurrent disease, options include resection with IORT f close positive margins, tum-directed RT with ( without) chemotherapy, chemotherapy, best supptive care (see NCCN Palliative Care Guidelines), participation in a clinical trial. Patients who recur after second-line definitive therapy, either surgery RT, have a po prognosis. They can be treated with chemotherapy, best supptive care, be enrolled in a clinical trial. Systemic Therapy f Metastatic Disease Patients who develop distant metastases, either at initial presentation at relapse, are rarely curable. F highly selected patients with isolated distant metastases, occasional long-term survival has been repted with 1) surgical resection with ( without) IORT; 2) RT with ( without) concurrent chemotherapy; 3) chemotherapy (see CERV-10). F most of the other patients with distant metastases, appropriate treatment is either chemotherapy (see CERV-B) best supptive care. The palliation of pelvic recurrences in heavily irradiated sites that are not amenable to local pain control techniques to surgical resection is an unresolved clinical issue. Such sites are generally not responsive to chemotherapy. It is clinically challenging to adequately palliate the complications of pain and fistulae from such recurrences ( However, sht-courses of RT may provide symptomatic relief to patients with bone metastases, painful para-atic nodes, supraclavicular 109, 110 adenopathy. Chemotherapy has a limited role in prolonging survival in improving quality of life and is recommended f patients with extrapelvic metastases recurrent disease who are not candidates f RT exenterative surgery. Patients who respond to chemotherapy may achieve pain relief of a transient nature. If cisplatin was previously used as a radiosensitizer, combination platinum-based regimens are preferred over single agents in the metastatic disease setting based on 111, 112 several randomized phase III trials (see next paragraph). First-Line Combination Chemotherapy Cisplatin has been considered the most effective agent f metastatic cervical cancer. 113 However, most patients who develop metastatic disease have received concurrent cisplatin/rt as primary treatment 111, 112 and may no longer be sensitive to single-agent platinum therapy. Cisplatin-based combination chemotherapy regimens, such as cisplatin/paclitaxel and cisplatin/topotecan, have been extensively investigated in clinical studies. 111, 112, A randomized phase III study (GOG 169) in 264 eligible patients comparing paclitaxel and cisplatin versus cisplatin alone showed that the 2-drug combination had a higher response rate (36% versus 19%) and improved progressionfree survival (4.8 versus 2.8 months; P>.001), although no improvement was seen in median survival. 111 F patients who responded to cisplatin/paclitaxel, there was a significant improvement in quality of life. Although carboplatin/paclitaxel has not been studied in a prospective randomized setting, many physicians used carboplatin/paclitaxel because of ease of administration and tolerability. Another randomized phase III GOG study (GOG 179) investigated the combination of cisplatin and topotecan versus cisplatin alone in recurrent persistent cervical cancer. In this study of 294 eligible patients, the topotecan combination regimen was shown to be superi to single-agent cisplatin with respect to overall response rate (27% versus 13%, P =.004), progression-free survival (4.6 versus 2.9 months; P=.014), and median survival (9.4 versus 6.5 months, P=.017). 112 The FDA has approved cisplatin/topotecan f advanced cervical cancer. However, the cisplatin/paclitaxel Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-8

31 carboplatin/paclitaxel regimens are less toxic and easier to administer when compared with cisplatin/topotecan. A recent phase III trial (GOG 204) in 513 patients with advanced metastatic recurrent cancer assessed 4 cisplatin-doublet regimens (cisplatin/paclitaxel, cisplatin/topotecan, cisplatin/gemcitabine, versus cisplatin/vinelbine). 116 The trial was closed early, because it was apparent that cisplatin/topotecan, cisplatin/gemcitabine, and cisplatin/vinelbine were not superi to cisplatin/paclitaxel. No significant differences in overall survival were seen; however, the trends f response rate, progression-free survival, and overall survival (12.9 versus 10 months) suggest that cisplatin/paclitaxel is superi to the other regimens. Cisplatin/paclitaxel was associated with less thrombocytopenia and anemia (but with me nausea, vomiting, infection, and alopecia), than the other regimens. Although cisplatin/gemcitabine was not shown to be a superi regimen in GOG 204, it was tolerable. Based on a phase III randomized trial f locally advanced cervical cancer, cisplatin/gemcitabine is included as an option in the NCCN guidelines. 61 Cisplatin/gemcitabine may be a useful regimen f patients with neuropathy who cannot tolerate other regimens. Many clinicians prefer using carboplatin rather than cisplatin because of ease of administration, tolerability, and preservation of renal function. A retrospective trial assessing cisplatin/paclitaxel versus carboplatin/paclitaxel confirmed these opinions. 117 Paclitaxel and carboplatin have been assessed f recurrent persistent cancer of the cervix. In a study using paclitaxel and carboplatin in 25 women, the median overall survival was 21 months. 118 Recently, a study using paclitaxel and carboplatin in 51 women had an median overall survival of 13 months. 119 A phase III trial assessing carboplatin/paclitaxel versus cisplatin/paclitaxel is currently in progress. 120 Non-platinum doublets are also being studied. 121 Single Agents Cisplatin is generally regarded as the most active agent and is recommended as possible first-line single agent chemotherapy in recurrent metastatic cervical cancer; repted response rates are approximately 20% to 30%, with an occasional complete response. 111,113, 122, 123 Overall survival with cisplatin is about 6-9 months. Carboplatin paclitaxel have been repted to be tolerable and efficacious and are also possible first-line single agent chemotherapy Therefe, palliation with single agents cisplatin, carboplatin, paclitaxel is a reasonable approach in patients with recurrent disease not amenable to surgical radiotherapeutic approaches. Complete responses were also observed with topotecan paclitaxel; however, topotecan is associated with me toxicity than carboplatin paclitaxel. Other agents (these are categy 2B unless otherwise indicated) that have shown responses prolongation of PFS and may be useful as second-line therapy include bevacizumab, 128 docetaxel, FU, 130 gemcitabine, 131 ifosfamide, 132, 133 irinotecan, 134 mitomycin, 135 topotecan, 136, 137 pemetrexed (categy 3), 138 and vinelbine (categy 3). 139 Drug Reactions Virtually all drugs have the potential to cause adverse reactions, either during after the infusion. 140 In cervical cancer treatment, drugs that me commonly cause adverse reactions include carboplatin, cisplatin, docetaxel, liposomal doxubicin, and paclitaxel. Most of these drug reactions are mild infusion reactions (i.e., skin reactions, cardiovascular reactions, respiraty throat tightness), but me severe allergic reactions (i.e., life-threatening anaphylaxis) can occur. 141, 142 In addition, patients can have severe infusion reactions and mild allergic reactions. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-9

32 Infusion reactions are me common with paclitaxel. 143 Allergic reactions (i.e., true drug allergies) are me common with platinum 143, 144 agents (i.e., carboplatin, cisplatin). Management of drug reactions is discussed in the NCCN Ovarian Cancer guidelines (see OV-C). 143 It is imptant to note that patients who have had severe life-threatening reactions should not receive the implicated agent again. If a mild allergic reaction has previously occurred and it is appropriate to administer the drug again, a desensitization regimen should be used even if the symptoms have resolved; various desensitization regimens have been published and should be followed Patients must be desensitized with each infusion if they previously had a reaction. Almost all patients can be desensitized. 140 To maximize safety; patients should be desensitized in the intensive care unit. 140 Other Agents Vaccine therapies have no established role in the treatment of cervical cancer at the present time, except in the setting of a clinical trial Targeted therapy (using small molecules monoclonal antibodies) is 60, 128, 150, 151 currently in clinical trials. Best Supptive Care Patients with refracty systemic cancer warrant a comprehensive codinated approach involving hospice care, pain consultants, and emotional and spiritual suppt, suited to the individual situation (see NCCN Palliative Care Guidelines). Incidental Invasive cervical carcinoma is sometimes found incidentally after extrafascial hysterectomy. Wkup f these patients includes histy and physical examination, complete blood count (including platelets), and liver and renal function tests. Radiologic imaging includes chest radiography, CT combined PET-CT, MRI as indicated (e.g., to rule out disease high in the endocervix); although imaging is optional f patients with stage IB1 smaller tums (see CERV-7). No definitive data exist regarding the appropriate primary treatment of these patients. The panel believes that a reasonable treatment schema f patients with either stage IAI with LVSI with stage 1A2 higher tums (pathologic findings) should be based on the status of the surgical margins. If margins are positive and imaging is negative f nodal disease, then pelvic RT with concurrent cisplatin-containing chemotherapy with without individualized brachytherapy should be recommended (see CERV-7). Stage 1A1 patients with no LVSI should undergo surveillance. If margins imaging is negative in stage 1A2 greater tums, options include (1) pelvic RT with ( without) concurrent cisplatincontaining chemotherapy and brachytherapy; (2) a complete parametrectomy, upper vaginectomy, and pelvic lymph node dissection with ( without) para-atic lymph node sampling. Patients with negative lymph nodes should be observed treated with optional pelvic radiation with ( without) vaginal brachytherapy if they have high-risk facts (i.e., large primary tum, deep stromal invasion, and/ LVSI (see CERV-7). 83 Concurrent cisplatin-based chemadiation is recommended f gross residual disease, positive imaging, disease in the lymph nodes and/ parametrium, and/ a positive surgical margin; individualized brachytherapy is clearly indicated f a positive vaginal margin. Radiation Therapy Radiotherapy is often used in the management of patients with cervical cancer, either f patients with intact cervical cancer who are not Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-10

33 amenable to surgery (e.g., definitive therapy f those with locally advanced disease f those who are po operative candidates), in patients following radical hysterectomy (i.e., adjuvant RT) who have one me pathologic risk facts (e.g., positive lymph nodes, parametrial infiltration, positive surgical margins, large tum size, deep stromal invasion, lymphovascular space invasion). The NCCN algithm provides general RT dosage recommendations, which are expanded upon in the Principles of RT section (see CERV-A). These RT dosages should not be interpreted as stand-alone recommendations, because RT techniques and clinical judgment are an essential part of developing an appropriate treatment regimen. Optimum staging of patients to precisely delineate the primary tum volume and draining lymph nodes, including abdominopelvic radiologic studies (CT, MRI, combined PET-CT scans), is recommended in patients with stage IB2, IIA2, advanced-stage tums. Contempary imaging studies must be crelated with careful assessment of clinical findings to define tum extent, especially with regard to vaginal parametrial extension. Radiation Treatment Planning Technological advances in imaging, computer treatment planning systems, and linear accelerat technology have provided the capability to me precisely deliver radiation dose to the pelvis. However, physical accuracy of dose delivery must be matched to a clear understanding of tum extent, potential pathways of spread, and histical patterns of local-regional recurrence to avoid geographic misses. CT-based treatment planning with confmal blocking and dosimetry is considered standard of care f external-beam radiotherapy. Brachytherapy is a critical component of therapy in patients with intact cervical cancer and is typically combined with external-beam radiation in an integrated treatment plan. F patients with locally advanced cancers, initial radiation treatment of Gy to the whole pelvis is often necessary to obtain tum shrinkage to permit optimal intracavitary placements. With low-doserate intracavitary systems, total doses from brachytherapy and externalbeam radiation to point A of at least 80 Gy are currently recommended f small tums, with doses of 85 Gy higher recommended f larger tums. F lesions in the lower one third of the vagina, the inguinal lymph nodes need to be treated. The use of extended-field radiation to treat occult macroscopic para-atic lymph node disease needs to be carefully planned to ensure an adequate dose (45 Gy f microscopic disease) without exceeding bowel, spinal cd, renal tolerances. 152 General recommendations f radiation volumes and doses are discussed in the algithm (see CERV-A). Intensity-modulated radiotherapy (IMRT) is becoming me widely available; however, issues regarding target definition, patient and target immobilization, tissue defmation and reproducibility remain to be validated The role of IMRT in cervical cancer continues to be actively evaluated in several prospective multicenter clinical trials. Several retrospective analyses have suggested an adverse effect of prolonged treatment duration on outcome Extending the overall treatment beyond 6 to 8 weeks can result in approximately a 0.5% to 1% decrease in pelvic control and cause-specific survival f each extra day of overall treatment time. Thus, although no prospective randomized trials have been done, it is generally accepted that the entire RT course (including both external beam and brachytherapy Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-11

34 components) should be completed in a timely fashion (within 8 weeks); delays splits in the radiation treatment should be avoided whenever possible. Nmal Tissue Considerations Planning f radiotherapy in cervical cancer must take into account the potential impact on surrounding critical structures, such as rectum, bladder, sigmoid, small bowel, and bone. Acute effects (i.e., diarrhea, bladder irritation, fatigue) occur to some degree in most patients undergoing radiation and are typically magnified by concurrent chemotherapy. However, acute effects are often manageable by medications and supptive care, and they generally resolve soon after completion of radiation. The risk of me significant late effects (i.e., obstruction, fibrosis/necrosis, fistula) is related to the volume, total dose, dose per fraction, and specific intrinsic radiosensitivity of the nmal tissue irradiated. 152 Careful blocking to minimize nmal tissue exposure while not compromising tum coverage is critical to achieving optimal outcomes. In addition, patient-related conditions (i.e., inflammaty bowel disease, collagen-vascular disease, multiple abdominal/pelvic surgeries, histy of pelvic inflammaty disease, diabetes) influence determination of radiation dose and volumes. F most patients, it is generally accepted that the whole pelvis can tolerate an external-beam radiation dose of Gy. Gross disease in the parametria unresected nodes may undergo tightly contoured external beam boosts to Gy. Intracavitary brachytherapy boosts require attention to proper placement of the applicats within the uterus and against the cervix and vaginal apex, as well as appropriate packing to maximally displace the bladder and rectum. Pregnancy and F pregnant women, cervical cancer is the most frequently diagnosed type of cancer; however, most pregnant women with cervical cancer have stage I disease. 163 Invasive cervical cancer during pregnancy creates a clinical dilemma. Women need to make the difficult decision either to delay treatment until documented fetal maturity to receive immediate treatment based on their stage of disease. F women diagnosed with cervical cancer during pregnancy who wish to continue their pregnancies, delaying cancer treatment until the fetus has matured has been repted. 163 Women who delay treatment until fetal maturity should have their children delivered by cesarean section. Patients with early stage disease may prefer to have radical hysterectomy and node dissection instead of RT to avoid radiation fibrosis and to preserve their ovaries. Those patients with early stage disease who delay treatment until fetal maturity can undergo cesarean section with radical hysterectomy and pelvic node dissection. F those opting f RT, traditional RT with ( without) chemotherapy protocols (which have been previously described) may need modification. 163 Vaginal radical trachelectomy has been successfully perfmed in a few pregnant patients with early stage cancer Summary Cervical cancer is decreasing in the United States, because screening has been widely used; however, cervical cancer is increasing in developing countries (about 270,000 deaths/year), because screening is not available to many women. Effective treatment f cervical cancer (i.e., surgery, concurrent chemo/rt) can yield cures in 80% of women with early stage disease (stages I and II) and in 60% of women with stage III disease. Hopefully, immunization against HPV (using the new vaccines) will prevent persistent infection with certain types of HPV 11, 12, 168 and, thus, is expected to prevent specific HPV cancer in women. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-12

35 Table 2: Estimates of the Relative Risk of Death in Five Clinical Trials of Concurrent Chemotherapy and Radiotherapy. Study FIGO Stage Control Group Comparison Group Relative Risk of Death in Comparison Group Keys et al.* IB2 Radiotherapy Radiotherapy plus weekly cisplatin 0.54 Rose, Bundy, Watkins et al.* IIB-IVA Radiotherapy plus hydroxyurea Radiotherapy plus weekly cisplatin Radiotherapy plus cisplatin, fluouracil, and hydroxyurea Mris et al.* IB2-IVA Extended-field radiotherapy Whitney et al. IIB-IVA Radiotherapy plus hydroxyurea Radiotherapy plus cisplatin and fluouracil Radiotherapy plus cisplatin and fluouracil Peters et al. IB IIA (selected postoperatively) Radiotherapy Radiotherapy plus cisplatin and fluouracil 0.50 Abbreviation: FIGO, International Federation of Gynecology and Obstetrics. *These studies have been updated (see ). Used with permission, from: Thomas GM. Improved treatment f cervical cancer concurrent chemotherapy and radiotherapy. N Engl J Med 1999;340(15): Copyright 1999 Massachusetts Medical Society. All rights reserved. Version , 10/06/10 National Comprehensive Cancer Netwk, Inc. 2010, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-13

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