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Expert Reviews Gynecology ajog.org
Changing paradigms in the systemic treatmentof advanced cervical cancerKrista S. Pfaendler, MD; Krishnansu S. Tewari, MD
Despite availability of primary and secondary prevention measures, cervical cancerpersists as one of the most common cancers among women around the world. Althoughearly-stage disease can be cured with radical and even fertility-sparing surgery, patientswith metastatic and recurrent cervical cancer have poor prognosis with historicallylimited treatment options and incurable disease. Significant advances in cervical cancertreatment have emerged as the result of clinical trials that have sought to determine thebest therapy to prolong overall and progression-free survival. Most recently, trials thathave involved angiogenesis blockade in addition to standard chemotherapy havedemonstrated improved overall and progression-free survival. This review serves tohighlight pivotal trials in chemotherapy development for advanced, metastatic, andrecurrent cervical cancer that includes the paradigm-shifting work that demonstratesincreased overall survival with angiogenesis blockade.
Key words: antiangiogenesis, bevacizumab, cervical cancer
ervical cancer is diagnosed in
C 528,000 women annually and re-sults in 266,000 deaths worldwide eachyear.1 The American Cancer Society esti-mates that there will be 12,900 new di-agnoses and 4100 cervical cancer-relateddeaths in the United States in 2015.2 Cer-vical cancer is 1 of many cancers caused byhuman papillomavirus (HPV) infection,but it is the only cancer for whichHPV has been demonstrated to be thenecessary precursor.3-5 Risk factors forcervical cancer are those associated withHPV exposure, such as an increasednumber of sexual partners, although ciga-rette smoking and immunosuppressionincrease risk of HPV persistence.6 Despitehigh efficacy and availability of HPV vac-cines3,7,8 and the recommendation forFrom the Division of Gynecologic Oncology (both aMedical Center (Dr Tewari), University of California,
Received April 21, 2015; revised July 12, 2015; ac
Supported by a National Institutes of Health T-32 tResearch Service Award Institutional Training Rese
Dr Tewari has reportedworking as a consultant for Rthe advisory board of Roche/Genentech, Caris, Advof Vermillion; and performing contracted researchZeneca. Dr Pfaendler has no conflicts of interest.
Corresponding author: Krishnansu S. Tewari, MD.
0002-9378/$36.00 � ª 2016 Elsevier Inc. All rights reser
22 American Journal of Obstetrics & Gynecology
routine vaccination,9 completion of thevaccine series among adolescent girls13-17 years old in the United States re-mains <40%.10 Given difficulties of theachievement of widespread compliancewith HPV vaccination and the inabilityto include all oncogenic subtypes in thevaccines, the importance of continuedsecondary prevention remains. Mostwomen who are diagnosed with cervicalcancer report an inability to recall whenthey last had a Papanicolaou smear or thatit was at least 10 years earlier; however,even among women compliant withscreening guidelines, cervical cancer maydevelop.11
Although the goals for HPV vacci-nation, Papanicolaou smears, andHPV testing are prevention and early
uthors), University of California, Irvine, IrvineOrange, CA.
cepted July 17, 2015.
raining grant (Ruth L. Kirschstein Nationalarch Grant, 2T32 CA-060396-11).
oche/Genentech, Caris, and Advaxis; serving onaxis, Vermillion; serving on the speaker’s bureaufor Genentech, Amgen, Endocyte, and Astra-
ved. � http://dx.doi.org/10.1016/j.ajog.2015.07.022
JANUARY 2016
diagnosis, approximately 5% of womenwho are diagnosed with cervicalcancer in North America have stage IVdisease12 with 5-year survival rates of9.3-21.6%.13 Even among women withearlier stages at diagnosis, 15-61% willexperience metastatic disease, usuallywithin the first 2 years of completingtreatment. For women who are diag-nosed with recurrent disease, 5-yearsurvival is <5%.12 This review focuseson changes in systemic treatment forwomen with metastatic or recurrentcervical cancer.
Development of standardchemotherapySingle-agent cisplatin was estab-lished as the backbone of chemotherapytreatment for advanced cervical cancer>30 years ago when a phase II trial ofcisplatin 50 mg/m2 demonstrated a 44%objective response rate (RR) in 25treatment-naïve patients.14 In a Gyne-cologic Oncology Group (GOG) phaseIII study of cisplatin with or withoutpaclitaxel for stage IVB, recurrent orpersistent squamous cell carcinoma ofthe cervix (GOG 169) is an objectiveresponse that occurred in 19% of pa-tients who received cisplatin vs 36% ofpatients who received cisplatin withpaclitaxel (Table 1).15 There was a sig-nificant increase in median progression-free survival (PFS); however, there wasno difference in overall survival (OS),and patients in the doublet arm experi-enced increased grade 3-4 anemia andneutropenia.
Phase II reports of high RR with theuse of methotrexate, vinblastine, doxo-rubicin and cisplatin (MVAC) promp-ted the development of GOG 179, arandomized phase III trial thatcompared MVAC with cisplatin plustopotecan or cisplatin alone.16 TheMVAC arm was closed by the DataSafety Monitoring Board because of4 treatment-related deaths among
TABLE 1Pivotal trials that contributed to chemotherapy standards for advanced, metastatic,and recurrent cervical cancer
TrialLeadauthor Eligibility Arms
Relativerisk (%)
Meanoverallsurvival,mo
Meanprogression-free survival,mo Conclusion
GynecologicOncology Group
169 Moore15 Stage IVB,recurrent orpersistent SCC
Cisplatin 50 mg/m2 19 8.8 2.8 Combined regimen superiorfor response rate andprogression-free survivalwithout detriment to qualityof life
Cisplatin 50 mg/m2 þpaclitaxel 135 mg/m2
36 9.7 4.8 No change in overall survival
179 Long16 Stage IVB,recurrent orpersistent
Cisplatin 50 mg/m2 13 6.5 2.9 Improved overall survivalwith doublet
Cisplatin 50 mg/m2 þtopotecan 0.75 mg/m2
day 1-3
26 9.4 4.6 Results most favorable forpatients with no previousradiosensitizing cisplatin
Methotrexate 30 mg/m2
days 1, 15, 22 þ vinblastine3 mg/m2 days 2, 15, 22 þdoxorubicin 30 mg/m2 day 2þ cisplatin 70 mg/m2 day 2
N/A N/A N/A
204 Monk17 Stage IVB,recurrent orpersistent
Cisplatin 50mg/m2 þ paclitaxel135 mg/m2
29 12.9 5.8 Closed for futility
Cisplatin 50 mg/m2 þtopotecan 0.75 mg/m2
days 1-3
23.4 10.3 4.7
Cisplatin 50 mg/m2 þgemcitabine 1000 mg/m2
22.3 10.3 4.6
Cisplatin 50 mg/m2 þvinorelbine 30 mg/m2
25.9 10 4.0
Japan ClinicalOncology GroupStudy 0505
Kitagawa20 Stage IVB,recurrent orpersistent
Cisplatin 50 mg/m2 þpaclitaxel 135 mg/m2
58.8 18.3 6.9 Noninferiority of carboplatin/paclitaxel doublet except inplatinum-naı̈ve patients
Carboplatin AUC 5mg/mL/min þpaclitaxel 175 mg/m2
62.6 17.5 6.2
AUC 5, area under the concentration vs time curve 5; N/A, not applicable (study arm closed early after 4 treatment-related deaths); SCC, squamous cell carcinoma.
Pfaendler. Changing paradigms in the systemic treatment of advanced cervical cancer. Am J Obstet Gynecol 2016.
ajog.org Gynecology Expert Reviews
63 patients. Among the remainingpatients who were assigned randomlyto cisplatin or cisplatin plus topotecan,patients who received the doublethad improved RR (27% vs 13%), me-dian PFS (4.6 vs 2.9 months), andmedian OS (9.4 vs 6.5 months) andmore grade 3 and 4 hematologic
toxicity, although without detriment toquality of life. This seminal study wasthe first randomized phase III trialto demonstrate statistically significantincreased survival with combinedchemotherapy over cisplatin alone fortreatment of advanced or recurrentcervical cancer.
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After phase II trials showed promisefor a doublet of vinorelbine pluscisplatin, a phase III trial (GOG 204) wasplanned with 2 arms that comparedpaclitaxel-cisplatin with vinorelbine-cisplatin; however, 2 additional armsthat compared gemcitabine-cisplatinand topotecan-cisplatin were added
merican Journal of Obstetrics & Gynecology 23
Expert Reviews Gynecology ajog.org
when phase II data for gemcitabine-cisplatin and phase III data fortopotecan-cisplatin became available.After a planned interim analysis, thestudy was closed for futility. This phaseIII trial showed that vinorelbine-cisplatin, gemcitabine-cisplatin, andtopotecan-cisplatin were not superior topaclitaxel-cisplatin in RR, OS, or PFSand that there was no difference inquality of life between study arms.17
Despite improvements in cisplatin-based combination chemotherapy, RRremained low for advanced cervicalcancer, which prompted a multivariatelogistic regression analysis of data fromGOG 110, 169, and 179 that identified 5risk factors for poor response to therapy:black race, performance status>0, pelvicdisease, previous radiosensitizer, andtime interval from diagnosis to firstrecurrence <1 year. The authors devel-oped a simple prognostic index thatcombined risk factors to create 3 groups:low risk (0-1 risk factor), mid risk (2-3risk factors) and high risk (4-5 risk fac-tors) and validated the index with the useof data from GOG 149.18
It has been suggested that therapeuticequivalency of cisplatin-paclitaxel (PT)and carboplatin-paclitaxel (CT) that isdemonstrated in ovarian cancer may beextrapolated to cervical cancer. To eval-uate this hypothesis, the Japanese Clin-ical Oncology Group developed amulticenter, open label, randomizedphase III trial to evaluate efficacy, safety,and quality of life of CT compared withPT.19MedianOSwas 18.3months for PTvs 17.5 months for CT (hazard ratio[HR], 0.994; 90% confidence interval[CI], 0.79e1.25), which demonstratedthe noninferiority of CT with signifi-cantly longer proportion of non-hospitalization periods for patients whoreceive CT (P < .001). Median PFS was6.9 months for PT vs 6.2 months for CT(HR, 1.041; 95% CI, 0.803e1.351).Among patients with no previouscisplatin treatment, OS was shorter withCT (13.0 vs 23.2 months; HR, 1.571;95% CI, 1.06e2.32), which indicatesthat cisplatin remains superior for plat-inum-naïve patients.20
Over the past 30 years, cisplatin-basedcombination chemotherapy has been
24 American Journal of Obstetrics & Gynecology
shown to produce the best PFS15,16 andOS16,20 for most patients with advancedand recurrent cervical cancer, with ex-ceptions for those with high risk fornonresponse to cisplatin based oncriteria of Moore et al.18 Despite exten-sive research to improve chemotherapyfor advanced and recurrent cervicalcancer, OS continues to be measured inmonths. For this reason, investigationsin recent years have delved into otherpathways in the hope of elicitingimproved response to treatment withprolongation of survival.
Angiogenesis blockadeHistorically, options have been limitedfor patients with persistent or recurrentcervical cancer after platinum-basedchemotherapy.14-18,21,22 Angiogenesis,the process of new blood vessel forma-tion, is essential not only for growth ofnew tissue, wound healing, andembryogenesis but also is fundamentalfor tumor proliferation. Vascular endo-thelial growth factor (VEGF) is the ma-jor mediator of tumor angiogenesis.23
Neovascularization correlates directlywith disease spread and inversely withsurvival. Ferrara et al24 developed bev-acizumab, a humanized anti-VEGFmonoclonal antibody that bound withan affinity comparable with that of theoriginal antibody. Bevacizumab wasthe first angiogenesis inhibitor to beapproved by the Food and DrugAdministration (FDA) for cancertreatment.23
BevacizumabIn a retrospective case series of 6 patientswith heavily pretreated recurrent cervicalcancer, 5 of the 6 patients received5-fluorouracil in combination withbevacizumab, and 1 of the 6 patientsreceived capecitabine with bevacizumab(Table 2).25 Among these 6 patients,complete response (17%; n ¼ 1), partialresponse (17%; n ¼ 1), or stable disease(33%; n ¼ 2) was seen among 67%(n¼ 4), which demonstrates encouragingantitumor activity with minimal grade 4adverse events (1 patient experiencedneutropenic sepsis). Among the 4 patientswhose condition demonstrated clinicalbenefit, median PFS was 4.3 months.
JANUARY 2016
An early case series by Wright et al25
suggested that bevacizumab in combi-nation with chemotherapy was active inrecurrent cervical cancer. A phase IIstudy to evaluate bevacizumab mono-therapy in this population was activatedthrough the Gynecologic OncologyGroup (ie, GOG 227C).26 Among the 46women who were enrolled, 82.6% (n ¼38) had received previous radiation, and1 (n ¼ 34; 73.9%) or 2 (n ¼ 12; 26.1%)previous cytotoxic regimens for recur-rent disease. Eleven of the 46 patients(23.9%; 2-sided 90% CI, 14e37%)achieved PFS for at least 6 months, andanother 5 patients (10.9%; 2-sided 90%CI, 4e22%) achieved partial response.Median PFS of 3.40 months (95% CI,2.53e4.53 months) and OS of 7.29months (95% CI, 6.11e10.41 months)with bevacizumab compared favorablywith other phase II trials for persistent orrecurrent disease, which prompted thedevelopment of a phase III trial.26
Because bevacizumab had demon-strated clinical activity in pretreatedpopulations, the Radiation TherapyOncology Group designed a phase IIsingle-arm study (protocol 0407) ofbevacizumab in addition to standardchemoradiation for bulky stage IB-IIIBcervical cancer to investigate efficacyand safety.27 Among the 60 patientsenrolled, 49 cases were evaluable and hada median follow-up time of 12.4 months(range, 4.6e31.4 months) with noserious adverse events.27 This study wasnot powered for PFS or OS analysis;however, in a report of secondary end-points, over a median follow-up time of3.8 years (range, 0.8e6.0 years), the 3-year OS was 81.3% (95% CI,67.2e89.8%), and the PFS was 68.7%(95% CI, 53.5e79.8%).28 This phase IItrial indicated that further study of bev-acizumab for treatment of locallyadvanced disease is warranted.
In a multicenter phase II trial thatevaluated a regimen of topotecan,cisplatin, and bevacizumab for persistentor recurrent cervical cancer, 27 patientswith no previous chemotherapy forrecurrence received a median of 3 treat-ment cycles (range, 1e19 cycles) anda median of 10 months (range, 1.7e33.4months) of follow up.29 Among the
TABLE 2Bevacizumab in cervical cancer treatment
Caseseries Lead author
Pathologiccondition Arms
Responserate, %
Overallsurvival,mo
Meanprogression-free survival,mo Conclusion
Wright25 SCC, AS 5-fluorouracil 250-500 mgIV every week þ bevacizumab5-15 mg/kg IV every 2-3wks
33 5.1 None reported Bevacizumab iswell-tolerated anddisplays antitumoractivity in recurrentcervical cancer
Capecitabine 2000 mg orallytwice daily þ bevacizumab5-15 mg/kg IV every 2-3wks
GynecologicOncologyGroup 227C
Monk26 SCC, AS Bevacizumab 15 mg/kgIV every 3 wks
35 7.3 3.4 Bevacizumab iswell-toleratedand active as second-and third-line therapyfor recurrent cervicalcancer and warrantsa phase III trial
RadiationTherapyOncologyGroup 0417
Schefter27,28 SCC Cisplatin 40 mg/m2 þ RTþ brachytherapy þbevacizumab 10 mg/kgevery 2 wks for 3 cycles
Nonereported
3-year;81.3%
3-year; 68.7% Bevacizumab in addition tostandard chemoradiation forlocally advanced cervicalcancer is feasible and safe
Zighelboim29 SCC, AC Cisplatin 50 mg/m2 day 1 þtopotecan 0.75 mg/m2 days1-3 þ bevacizumab 15 mg/kgday 1 every 3 wks
35 13.2 7.1 Addition of bevacizumab tocisplatin and topotecanproduces an active by highlytoxic regimen
GynecologicOncologyGroup 240
Tewari30 SCC, AS,or AC
Cisplatin 50 mg/m2 þ paclitaxel135 or 175 mg/m2
14.3 5.9 Bevacizumab resulted in3.7-month increased overallsurvival (17 mo comparedwith 13.3 mo)
Cisplatin 50 mg/m2 þ paclitaxel135 or 175 mg/m2 þbevacizumab 15 mg/kg
17.5 8.2
Topotecan 0.75 mg/m2 days 1-3þ paclitaxel 175 mg/m2
12.7
Topotecan 0.75 mg/m2 days1-3 þ paclitaxel 175 mg/m2
þ bevacizumab 15 mg/kg
16.2
AC, adenocarcinoma; AS, adenosquamous carcinoma; IV, intravenously; RT, pelvic radiotherapy; SCC, squamous cell carcinoma.
Pfaendler. Changing paradigms in the systemic treatment of advanced cervical cancer. Am J Obstet Gynecol 2016.
ajog.org Gynecology Expert Reviews
26 evaluable cases, 59% (80% CI,46e70%) experienced 6-month PFS; 1patient (4%; 80% CI, 0.4e14%) expe-rienced complete response, and 8 pa-tients (31%; 80% CI, 19e45%)experienced partial response that lasteda median of 4.4 months. Median PFSwas 7.1 months (80% CI, 4.7e10.1months), and median OS was 13.2months (80% CI, 8.0e15.4 months).Unfortunately, grade 3-4 hematologic
toxicity was common with high inci-dence (78%) of unanticipatedhospitalizations.The first phase III randomized trial
(GOG 240) of bevacizumab foradvanced cervical cancer randomlyassigned women to 1 of 4 arms: (1)cisplatin plus paclitaxel, (2) cisplatin,paclitaxel, and bevacizumab, (3) top-otecan plus paclitaxel, and (4) topotecan,paclitaxel, and bevacizumab.30 Inclusion
JANUARY 2016 A
criteria included adequate hepatic, bonemarrow, and renal function and goodnutritional status. Most of the studygroup (75%) previously had receivedplatinum and were distributed evenlybetween the 2 backbones. Addition ofbevacizumab to chemotherapy resultedin a 3.7-month increase in median OS(17.0 vs 13.3 months; Figure 1) andhigher RR (48% vs 36%; P ¼ .008).Subanalysis showed beneficial effects of
merican Journal of Obstetrics & Gynecology 25
FIGURE 1Overall survival in Gynecologic Oncology Group 240 according tochemotherapy regimen
Overall survival among patients who were assigned to cisplatin-paclitaxel chemotherapy with or
without bevacizumab and those who were assigned to topotecan-paclitaxel chemotherapy with or
without bevacizumab.
Bev, bevacizumab; CI, confidence interval; HR, hazard ratio; mos, months; OS, overall survival.
From Massachusetts Medical Society. Reprinted with permission from Tewari KS et al.30
Pfaendler. Changing paradigms in the systemic treatment of advanced cervical cancer. Am J Obstet Gynecol 2016.
Expert Reviews Gynecology ajog.org
bevacizumab in patients who had beenexposed previously to platinum andamong those with recurrent or persistentdisease. Additionally, benefits of bev-acizumab were demonstrated in patientswith recurrent disease in a previouslyirradiated field. Grade 2 or higher hy-pertension, grade 3 or higher gastroin-testinal, or genitourinary fistulas andgrade 3 or higher thromboembolicevents were all significantly higheramong patients who received bev-acizumab, but quality-of-life scoresindicated that the addition of bev-acizumab did not affect health-relatedquality of life adversely. In the finalprotocol-specified OS analysis, bev-acizumab improved OS to 16.8 monthsvs 13.3 months for chemotherapy alone(HR, 0.765; 95% CI, 0.62e0.95; P ¼.0068).31
One exploratory objective of GOG240 was to validate pooled clinicalprognostic factors prospectively (criteriaof Moore et al18). High-risk patients (4-5 factors) had significantly worse OS (P< .0001). Hazard ratios of death fortreatment with topotecan in low-risk (0-1 factors), mid-risk (2-3 factors), andhigh-risk (4-5 factors) subsets were 1.18
26 American Journal of Obstetrics & Gynecology
(95% CI, 0.63e2.24), 1.11 (95% CI,0.82e1.5), and 0.84 (95% CI,0.50e1.42), respectively; HRs of deathfor treatment with bevacizumab in low-risk, mid-risk, and high-risk subsetswere 0.96 (95% CI, 0.51e1.83;P ¼ .9087), 0.673 (95% CI, 0.5e0.91;P ¼ .0094), and 0.536 (95% CI,0.32e0.905; P ¼ .0196), respectively.Toxicity concerns and lack of statisticallysignificant survival benefit in the low-risk group of patients may justify thereservation of bevacizumab for mid-riskand high-risk populations, unless largerstudies demonstrate benefit for the low-risk population.32
Other antiangiogenesis agentsOther antiangiogenic agents under studyinclude sunitinib, pazopanib, lapatinib,and cediranib (Table 3). Sunitinibmalateis an orally bioavailable small moleculethat inhibits members of the split-kinasedomain family of receptor tyrosine ki-nases, including VEGF and platelet-derived growth factor.33 Sunitinib isFDA approved for patients with meta-static renal cell carcinoma and gastroin-testinal stromal tumors. A multicenterphase II trial was performed to evaluate
JANUARY 2016
sunitinib in women with locallyadvanced or metastatic cervical carci-noma who had received up to 1 previousline of chemotherapy with a primaryendpoint of objective RR.34 Among 19patients who were enrolled in the study,16 patients had stable disease but noobjective response after a median dura-tion of 4.4months. Five patients (26.3%)experienced fistula, although 4 of thesepatients had received previous radiation,which made it difficult to determine thecontribution of sunitinib to fistuladevelopment. Regardless, this studyshowed that sunitinib does not havesufficient activity as a single agent incervical cancer.
A phase II open-label study of pazo-panib or lapatinib monotherapycompared with pazopanib plus lapatinibcombination therapy confirmed activityof antiangiogenesis agents in advancedand recurrent cervical cancer. Pazopanibis an oral angiogenesis inhibitor thattargets VEGF receptor, platelet-derivedgrowth factor receptor, and c-Kit and isFDA approved for use in metastatic softtissue sarcomas and metastatic renal cellcarcinoma. Lapatinib is an oral small-molecule dual tyrosine kinase inhibitorthat targets epidermal growth factor re-ceptor and human epidermal growthfactor receptor 2 (HER2/neu) and isFDA approved for use in combinationwith capecitabine for patients withadvanced or metastatic breast cancer.The combined arm in this study wasclosed for futility after interim analysis,but the trial demonstrated improved PFSfor pazopanib monotherapy comparedwith lapatinib monotherapy.35 Interimanalysis data indicated improved OS inthe pazopanib arm; however, the studywas not powered for OS, and finalanalysis failed to show any significantdifference.36
A randomized double-blind phase IItrial of CT plus cediranib vs CT plusplacebo in metastatic and recurrent cer-vical cancer was performed in the UnitedKingdom.37 Cediranib is a tyrosine ki-nase inhibitor of VEGF receptors 1, 2,and 3 and has been formulated as an oralmedication. The randomized double-blind phase II trial randomly assignedpatients to receive cediranib 20 mg or
TABLE 3Other antiangiogenesis agents in cervical cancer treatment
Trial Lead author Pathology ArmsResponserate, %
Overallsurvival,wk
Progression-freesurvival, wk Conclusion
NCIC CTGIND.184
Mackay34 SCC, AS,or AC
Sunitinib 50 mg orally,daily for 4 wks
0 Nonereported
24.6 Higher rate of fistulaformation (26.3%) thanexpected; insufficientactivity as single agent
Monk35,36 SCC, AS,or AC
Pazopanib 800 mg orally, daily 9 50.7 18.1 Pazopanib improvedprogression-free survivaland overall survival
Lapatinib 1500 mg orally, daily 5 39.1 17.1
CRUK/10/001 Symonds37 SCC, AS,or AC
Cediranib 20 mg orally,daily þ carboplatin AUC5þ paclitaxel 175 mg/m2
every 21 days
66 59 35 Addition of cediranib tocarboplatin and paclitaxelresults in prolongedprogression-free survivalwith no change in overallsurvival
Placebo daily þ carboplatinAUC5 þ paclitaxel 175 mg/m2
every 21 days
42 63 30
AC, adenocarcinoma; AS, adenosquamous carcinoma; AUC5, area under the concentration vs time curve 5; SCC, squamous cell carcinoma.
Pfaendler. Changing paradigms in the systemic treatment of advanced cervical cancer. Am J Obstet Gynecol 2016.
ajog.org Gynecology Expert Reviews
placebo daily in addition to carboplatinAUC5 and paclitaxel 175mg/m2 every 21days for a maximum of 6 cycles. MedianPFS was 30 weeks with placebo vs 35weeks with cediranib (HR, 0.61; 80% CI,0.41e0.89; P¼ .046). Median OS was 63weeks with placebo vs 59 weeks withcediranib (HR, 0.93; 80% CI, 0.64e1.36;P ¼ .401). RR was higher in those whoreceived cediranib (66% vs 42%; P ¼.030) as was toxicity; 19% of patientsexperienced grade 2-4 toxicity comparedwith 9% in the placebo group.
Antiangiogenesis agents other thanbevacizumab have failed to demonstratestatistically significant benefit in OS foradvanced and recurrent cervical cancer.A phase II study of sunitinib mono-therapy failed to show an objectiveresponse.34 Other phase II trials ofantiangiogenesis agents have demon-strated improved PFS with no benefitto OS. Pazopanib monotherapy showedimproved PFS compared with lapatinibmonotherapy but was not poweredto assess OS35,36; cediranib added to aCT chemotherapy backbone showedimproved PFS compared with placebo(35 vs 30 weeks) but no statistically sig-nificant difference in OS.37 Additional
phase II trials are needed to determinewhich antiangiogenesis agents mayproduce an OS benefit for patients withadvanced or recurrent cervical cancer.
Changing paradigmsAlthough women with advanced cer-vical cancer are at high risk forpersistence and recurrence, majorparadigm shifts have occurred in recentyears that have changed that outlookfor these women (Figure 2). The clin-ical, pathologic, and molecular ratio-nale to target VEGF is a proof ofconcept of antiangiogenesis therapy.Although a phase II trial of sunitinibfailed to show significant single-agentactivity for advanced or metastaticcervical cancer,34 a phase II open-labelstudy of pazopanib and lapatinibconfirmed activity of antiangiogenesisagents in advanced and recurrent cer-vical cancer.36 Addition of cediranib tocarboplatin and paclitaxel resulted in a5-week prolongation of PFS, althoughit had no significant impact on OS.37
These studies demonstrated potentialbenefit of antiangiogenesis therapy inthe treatment of advanced and recur-rent disease.
JANUARY 2016 A
Chemotherapy plus bevacizumabsignificantly improves OS, PFS, and RRwithout significant deterioration inhealth-related quality of life. Single-agent cisplatin was established as thebackbone of chemotherapy treatmentfor cervical cancer many years ago, butmore recent trials have shown a benefitfor chemotherapy doublets and morerecently with angiogenesis inhibitors.Although many trials have shownimproved RR or PFS for 1 chemotherapyregimen compared with another, rarelyhas improved OS be demonstrated.Recently, GOG 240 transformed treat-ment for advanced, recurrent, and met-astatic cervical cancer by demonstratingthat targeted agents can improve survivalsignificantly. The findings of GOG 240that revealed a 3.7-month increase in OSwith no significant deterioration inquality of life serves as proof of principlein the value of systemic therapy andproof of concept of the efficacy ofangiogenesis blockade therapy.30
The significant increase in OS withthe addition of bevacizumab tochemotherapy creates a potentialwindow of opportunity through whichpatients deriving benefit may be
merican Journal of Obstetrics & Gynecology 27
FIGURE 2Changing paradigms in advanced, metastatic and recurrent cervical cancer
The paradigm changes described in the text are given.
HRQoL, health-related quality of life; OS, overall survival; PFS, progression-free survival; RR, response rate; VEGF, vascular endothelial growth factor.
Pfaendler. Changing paradigms in the systemic treatment of advanced cervical cancer. Am J Obstet Gynecol 2016.
Expert Reviews Gynecology ajog.org
treated with other novel agents,including other classes of antiangio-genesis drugs, immunotherapy, poly-ADP-ribose polymerase 1 inhibitors,and mammalian target of rapamycininhibitors, thereby potentially extend-ing survival further.
28 American Journal of Obstetrics & Gynecology
Optimization of medical comorbid-ities, renal function, and nutritional sta-tus allows for proof of principle ofsystemic therapy. Patients who previ-ously were thought to be too sick tobenefit from systemic therapy experi-enced rapid deterioration in their quality
JANUARY 2016
of life and short survival after diagnosis.In GOG 204, the PT and topotecan-paclitaxel arms had an OS of 12.9 and10.3months, respectively.17 InGOG240,after optimization of medical comor-bidities, the PT and topotecan-paclitaxelarms without bevacizumab had an OS
ajog.org Gynecology Expert Reviews
of 14.3 and 12.7 months, respectively.30
Reducing medical comorbidities suchas improving renal function with the useof stents and nephrostomy tubes,improvement of performance statusthrough optimization of pain control,and correction of malnutrition canmakepatients eligible for systemic therapy andcontribute to prolonged OS.
Prospective validation of pooled clin-ical prognostic factors allows for riskstratification and estimation of treatmentefficacy.32 One of the objectives of GOG240was to validate prospectively the 5 riskfactors for poor response to cisplatin-based therapy that were identified byMoore et al.18 Median OS was notsignificantlydifferent for low-risk patientswho received bevacizumab in addition tochemotherapy; however, among high-risk patients, the median OS was 6.3months for chemotherapy alone vs 12.1months for chemotherapy with bev-acizumab. Although there was a clinicalbenefit for the receipt of bevacizumab inall groups, thosewith highest risk for poorresponse to cisplatin-based therapyderived the greatest benefit from the in-clusion of bevacizumab in their treatmentregimens.
Central failure after chemoradiationor radical surgery with adjuvant therapyis often accompanied by distant metas-tases, which precludes candidacy forpelvic exenteration.38 Isolated centralpelvic recurrences that lend themselvesto pelvic exenteration are becomingincreasingly rare in the era of concurrentchemoradiation plus brachytherapy.Although feasible and potentially cura-tive, pelvic exenteration has highmorbidity rates, even in the hands of anexperienced gynecologic oncologist.39
However, since the original introduc-tion of the procedure by Brunschwig in1948, technical advances such as the in-testinal conduit for urinary diversionand end-to-end anastomosis with theintestinal stapling device for preserva-tion of fecal stream have produced sig-nificant improvements in morbidity.38
The introduction of biosimilars islikely to lower the incremental cost-effectiveness ratio. Bevacizumab ther-apy adds $73,791 per 3.5 months of lifegained or $5775 per month of added life
and $24,597 per quality-adjustedlife month. A Markov model that wascreated based on GOG 240 indicatesthat cost reductions through availabilityof biosimilars result in declines inthe incremental cost-effectiveness ratio,because increased costs are largely directcosts because of the drug rather thanindirect costs for the management ofbevacizumab-induced complications.40
As biosimilars are introduced to themarket, the use of bevacizumab inadvanced and recurrent cervical cancerwill gain cost efficacy; however, it may bemany years before bevacizumab isaffordable for women in low- andmiddle-income countries where theoverwhelming majority of advancedcervical cancer cases occur.Minimally invasive liquid biopsies
allow for phenotypic interrogation andmay represent biomarkers with bothprognostic and predictive value.41,42 Theprimary translational research objectiveof GOG 240 was to determine whethercirculating tumor cells (CTCs) could beisolated from patients and whether CTCcounts would be associated with hazardof death. Median CTC count was 7CTCs/8.5mLwhole blood (range, 0e18)precycle 1 and 4 CTCs/8.5 mL wholeblood (range, 0e17) 36 days postcycle 1.The hazard of death for pretreatmentCTC counts was 0.9 (95% CI,0.81e0.99) within the cisplatin-paclitaxel-bevacizumab group, and pa-tients with greater declines had a lowerhazard of death (HR, 0.87; 95% CI,0.79e0.95).Feldman et al41 evaluated 592 cervical
cancer specimens in their repositoryusing next-generation sequencing, insitu hybridization, and immunohisto-chemistry. Mutational hotspots wereidentified that corresponded to PI3KCA(26%), BRCA2 (21%), BRCA1 (10%),KRAS (10%), TP53 (10%), and FBXW7(10%) with the use of next-generationsequencing on 224 specimens. Theyalso observed gene amplification (in situhybridization) of EGFR (20/174 speci-mens; 11%), and HER2 (32/395 speci-mens; 8%). Immunohistochemistrystudies showed overexpression of estro-gen receptor (118/590 specimens;20%), progesterone receptor (48/589
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specimens; 8%), and androgen receptor(22/578 specimens; 4%) in addition toother protein signatures. These datasuggest that theranostic biomarkersmay help to guide therapy for patientswhose condition does not respond toantiangiogenesis therapy. The next-generation sequencing, in situ hybridi-zation, and IHC results suggest thatPI3K/AKT/mechanistic target of rapamy-cin pathway inhibitors, EGFR- andHER2-directed therapy, immuno-therapy, and hormonal therapy may bepromising areas for future research.
Additional work is needed todevelop and test molecularly targeteddrugs and immune system modulationto achieve improved outcomes forwomen with persistent, metastatic, andrecurrent cervical cancer. Further studyof theranostic biomarkers may help toguide therapy for patients whose dis-ease progresses on antiangiogenesistherapy or is otherwise incurable.41
With continued exploration of theseavenues, new therapeutic paradigmsare likely to emerge that furtherimprove survival and quality of life inthis vulnerable population. -
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