Cervix landmark trials- kiran

LANDMARK CLINICAL
TRIALS IN CERVIX CANCER
Dr . Kiran Kumar BR
Reference:
1.Perez & Brady’s Principles and Practice of Radiation Oncology Seventh Edition
2.FIGO Cancer Report 2018

Out Line
• Early Lesions
• Locally Advanced Lesions
• Metastatic Setting
• Role of Neoadjuvant Chemotherapy

Early Lesions: Surgery Versus Radiation
Landoni et al. published results of a prospective, randomized trial of
radiation therapy versus surgery; 469 women with stage IB and IIA
cervical carcinoma were referred for treatment and 343 were
randomized (172 to surgery and 171 to radiation therapy).
Postoperative irradiation was delivered after surgery for women with
surgical stage pT2b or greater, <3 mm of cervical stromal invasion and
cut-through margins, or positive pelvic nodes.
Median follow-up was 87 (range 57–120) months.

Results The overall and disease-free actuarial 5-year survival for all patients were
83% and 74%, respectively, and did not differ significantly between the
groups.

After a median follow-up of 87 months (range, 57 to 120 months), 5-
year overall survival and DFS rates were nearly identical in the surgery
and radiation therapy groups (83% and 74%, respectively).
Recurrent disease developed in 86 women: 42 (25%) in the surgery
group and 44 (26%) in the radiation therapy group.
Forty-eight patients (28%) in the surgery group had severe morbidity,
compared with 19 (12%) in the radiation therapy group (P = .0004).
The combination of surgery and radiation therapy had the worst
morbidity, especially urologic complications.

5-year actuarial survival stratified by cervical diameter was similar in the surgery
and radiotherapy groups (diameter 4 cm: 87% vs 90%; diameter >4 cm: 70% vs
72%; figure 3, table 3).
5-year actuarial disease-free survival for the surgery and radiotherapy groups was
80% and 82%, respectively, for patients whose cervical diameter was 4 cm or
smaller, and 63% and 57% for those with a diameter larger than 4 cm; the
betweengroup differences were not significant.
The two groups did not differ significantly as regards squamous histological type:
overall 5-year survival rates were 84% in surgery-group patients and 88% in
radiotherapy-group patients; overall disease-free survival was 76% and 78%,
respectively.
For rates of adenocarcinoma there was a significant advantage for patients who had
surgery compared with those who had radiotherapy in both overall survival (70% vs
59%, p=0·05) and disease-free survival (66% vs 47%, p=0·02).

Conclusion
Most women with stage Ib–IIa cervical cancer can be treated successfully with radiotherapy, whereas
a judicious selection of patients is necessary before planning primary radical surgery.
Histological type should be included in the selection criteria, because our data show that radiotherapy
was less effective than surgery for adenocardinoma of the cervix. This finding should resolve some of
the conflicting approaches to this issue.
Results suggest that the optimum candidates for primary radical surgery are women with normal
ovarian function and cervical diameters of 4 cm or smaller, whereas radiotherapy is preferable for
postmenopausal women.
Women whose cervical diameters are larger than 4 cm should be identified before surgery so that
they can benefit from tailored treatment: radical radiotherapy, with the option of concomitant
radiosensitising chemotherapy to improve the local control of the disease, or cisplatin based
chemotherapy followed by radical surgery.

Randomized study between radical surgery and radiotherapy for
the treatment of stage IB–IIA cervical cancer: 20-year update
(2017)
Minimum follow-up was 19 years. Thirty-three patients (10%) died of intercurrent disease
(31 cases) or fatal complications (2 cases).
Twenty-year overall survival is 72% and 77% in the 2 treatment groups (p=0.280),
respectively.
Conclusion: The results of the study seem to suggest that there is no treatment of choice
for early stage cervical carcinoma in terms of survival. Long term follow-up confirms that
the best treatment for the individual patient should take into account clinical factors such as
menopausal status, comorbidities, histological type, and tumor diameter.

One randomized study showed improved recurrence-free survival with
postoperative pelvic irradiation (46 to 50.4 Gy in 23 to 28 fractions) after radical
surgery in the presence of positive pelvic nodes or node-negative high-risk factors in
women with stage IB cervical cancer treated by radical hysterectomy and pelvic
lymphadenectomy.
There were 277 eligible patients with at least two of the following risk factors:
greater than one-third stromal invasion, capillary lymphatic space involvement, and
large clinical tumor diameter; 137 patients were randomized to pelvic radiation
therapy and 140 to no further treatment.
The results were updated by Rotman et al. 24 (17%) patients in the irradiation group
and 43 (30.7%) in the no-further-treatment group had cancer recurrences.

In the radiation therapy group, 27 patients died of cancer, and in the no-
further treatment group 40 died from cancer. There was a statistically
significant reduction in risk of recurrence in the irradiation group, with
recurrence-free rates at 2 years of 88% versus 79% for the irradiation and no-
further-treatment groups, respectively.
Overall survival difference did not reach statistical difference (P = .074; Fig.
73.19). Severe or life-threatening (GOG grade 3 or 4) adverse effects
occurred in 9 patients (6.6%) in the radiation therapy group and 3 (2.1%) in
the observation group.
A meta-analysis of trials including stage IB1 to IIA cervical cancer found that
women who received postoperative radiation had a significantly lower risk of
disease progression at 5 years (RR = 0.6, 95% CI = 0.4 to 0.9).
The risk of serious adverse events was not significantly higher if women
received radiotherapy rather than no further treatment, possibly because the
rate of adverse events was low.

Southwest Oncology Group 8797 was a study for women with FIGO
stage IA2, IB, or IIA carcinoma of the cervix with metastatic disease in
the pelvic lymph nodes, positive parametrial involvement, or
positive surgical margins at the time of primary radical hysterectomy
with total pelvic lymphadenectomy.
Patients had confirmed negative PALNs; if the PALNs were not
sampled, the patients had confirmed negative common iliac lymph
nodes.

One hundred twenty-seven patients were randomized to treatment with
pelvic EBRT with 5- FU infusion and cisplatin, and 116 were treated
with irradiation alone.
The 3- year survival for women on the adjuvant cisplatin/5-FU and RT
arm was 87%, compared with 77% for women on the pelvic irradiation
arm.438 The difference was statistically significant.
An updated analysis with 5.2-year median follow-up reported 5-year
overall survival of 80% versus 66%, favoring postoperative
chemoradiation in high-risk patients

Trialsinthenon-metastaticsetting-LocallyAdvanced
Theadvent of chemo-radiation therapy
Prior to 1999 locally advanced(non- surgical/non-metastatic) cervical cancer was
treated with radiation therapyand intracavitary therapy
Long-term overall survival (OS)in stageIII wasabout 40-50%
That all changedonApril 15,1999…

Stage IB2 (>4 cm) Cervical
Cancer
N0 by CT/FNA/Surgery
PS 0-3
Suitable for hysterectomy
Adequate organ function
External Radiotherapy with
Concurrent weekly Cisplatin (40
mg/m2, max 70 mg, x6)
Intracavitary brachytherapy
Extrafascial hysterectomy*
Extrafascial hysterectomy*
Endpoints
PFS,OS
75 Gy to point A, 55 Gy to point B
*Extrafascial hysterectomy post
irradiation was deemed
necessary in 1992 when this
study was initiated. That is no
longer the case
GOG-123
Weekly Cisplatin Chemotherapy during Irradiation
Improves Survival and Reduces Relapses for
patients with Bulky Stage IB Cervical Cancer
Treated with Irradiation and Adjuvant Hysterectomy
Keys,H.M., Bundy, B.N., Stehman,F.B., Muderspach, L.I., Chafe,W. E.,Suggs,C.L.,…Gersell, D. (1999). Cisplatin, Radiation, and Adjuvant Hysterectomy
Comparedwith Radiation and Adjuvant Hysterectomy for Bulky Stage IB CervicalCarcinoma.New EnglandJournalof Medicine, 340(15), 1154–1161.
https://doi.org/10.1056/NEJM199904153401503

PFS(%)
79*
GOG-123
Weekly Cisplatin Chemotherapy during Irradiation Improves Survival and
Reduces Relapses for patients with
Bulky Stage IB Cervical Cancer Treated with Irradiation and Adjuvant
Hysterectomy
OS(%)- Median F/U of 36mo
85*
Concurrent chemo-RT
RT
74*
63*35* 15*
Grade¾toxicity
* Statisticallysignificant
96%
Underwent hysterectomy(%)
90
n=369
Keys,H.M., Bundy, B.N., Stehman, F.B., Muderspach, L.I., Chafe,W. E.,Suggs,C.L.,…Gersell, D. (1999). Cisplatin, Radiation, andAdjuvant
Hysterectomy Comparedwith Radiation and Adjuvant Hysterectomy for Bulky Stage IB CervicalCarcinoma.New EnglandJournal of Medicine,
340(15), 1154–1161.https://doi.org/10.1056/NEJM199904153401503

Stage IIB-IVA
or Stage IB or IIA (>5 cm)
or Biopsy-proven pelvic
metastasis
Cervical cancer
KPS >60%
External Radiotherapy with Concurrent
weekly
Cisplatin + Fluoruracil infusion q3w
RTOG 9001
Pelvic Radiation with Concurrent Chemotherapy
Compared with Pelvic and Para-Aortic Radiation for
High-Risk Cervical Cancer
Morris, M., Eifel, P.J., Lu, J., Grigsby, P.W., Levenback, C.,Stevens, R.E.,…Mutch, D. G.(1999). Pelvic Radiation
with Concurrent Chemotherapy Compared with Pelvic and Para-Aortic Radiation for High-Risk Cervical Cancer. New
England Journal of Medicine, 340(15), 1137–1143.https://doi.org/10.1056/NEJM199904153401501
Endpoints
OS PFS

Morris, M., Eifel, P. J., Lu, J., Grigsby, P. W., Levenback, C., Stevens, R. E., …Mutch, D. G. (1999). Pelvic Radiation with
Concurrent Chemotherapy Compared with Pelvic and Para-Aortic Radiation for High-Risk Cervical Cancer. New England Journal
of Medicine, 340(15), 1137–1143. https://doi.org/10.1056/NEJM199904153401501
PFSat 24mo(%)
RTOG-9001
Pelvic Radiation with Concurrent Chemotherapy Compared with Pelvic and Para-Aortic Radiation
for High-Risk Cervical Cancer
67*
73*
58*
65*
Locoregionaldiseasecontrol (%)
* Statistically significant
ConcurrentCisplatin/FU-RT
RT
40*79*
86*
Distant-metastasisfree(%)
67*
n=403

GOG 85 (Whitney et al.)
The GOG conducted randomized Protocol 85, in which patients with carcinoma of
the cervix, a clinical stage of IIB to IVA, and negative para-aortic nodes were treated
with external pelvic irradiation (51 Gy) combined with 30 Gy to point A with LDR
brachytherapy.
One hundred twenty- seven patients received 5-FU (IV infusion, 1 g/m2 for 4 days)
and cisplatin (50 mg/m2 IV) on days 1, 29, and 30 to 33.
191 patients received hydroxyurea (80 mg/kg orally twice weekly).
With a median follow-up for survivors of 8.7 years, the 5- year survival rate in the
cisplatin/5-FU arm was 60%, compared with 47% for women in the hydroxyurea
arm.

Stage IIB-IVA Cervical
cancer
N0 by CT and
lymphadenectomy
PS 0-3
External Radiotherapy with Concurrent
weekly
Cisplatin (40 mg/m2, max 70 mg, x6)
Concurrent hydroxyurea
Endpoints
OS PFS
RT dosages
Stage II: 80.8 Gy to point A, 55 Gy to point B
Stage III-IVA: 81 Gy to point A, 60 Gy to point B
GOG-120
Concurrent Cisplatin-Based
Radiotherapy and Chemotherapy for
Locally Advanced Cervical Cancer
Rose, P.G.,Bundy, B.N., Watkins, E.B., Thigpen, J.T., Deppe, G., Maiman, M. A., …Insalaco, S.(1999). Concurrent
Cisplatin- Based Radiotherapy and Chemotherapy for Locally Advanced Cervical Cancer. New England Journal of Medicine,
340(15), 1144–1153. https://doi.org/10.1056/NEJM199904153401502
Concurrent Cisplatin / FU /
Hydroxyurea

GOG-120: Concurrent Cisplatin-Based Radiotherapy and
Chemotherapy for Locally Advanced Cervical
Cancer
Rose,P.G.,Bundy, B.N., Watkins, E.B.,Thigpen,J.T., Deppe,G.,Maiman, M. A., …Insalaco, S.(1999). Concurrent Cisplatin-Based
Radiotherapy and Chemotherapy for LocallyAdvancedCervical Cancer.NewEnglandJournal of Medicine, 340(15), 1144–1153.

GOG 120: Concurrent Cisplatin-Based Radiotherapy and
Chemotherapy for Locally Advanced Cervical
Cancer
PFSat 24mo(%)
46*
67*
64*21*
Grade¾Leucopenia
* Statisticallysignificant
ConcurrentCisplatin-RT
ConcurrentCisplatin/FU/Hydroxyurea-RT
Concurrenthydroxyurea-RT
47*
67*
66*
49*
23*
n=526
Rose,P.G.,Bundy, B.N., Watkins, E.B.,Thigpen,J.T., Deppe,G.,Maiman, M. A., …Insalaco, S.(1999). Concurrent Cisplatin-Based
Radiotherapy and Chemotherapy for LocallyAdvancedCervical Cancer.NewEnglandJournal of Medicine, 340(15), 1144–1153.

Pearcey et al.
Pearcey et al. reported on a Canadian randomized study in which 127
patients with stage IB to IIA of >5 cm or IIB carcinoma of the cervix
were randomized to be treated with
1.cisplatin (40 mg/m2 weekly) and RT
2. 126 patients were treated with RT alone (50.4 Gy to the pelvis
combined with brachytherapy).
With a median follow-up of 65 months, the 5-year survival rates were
59% and 56%, respectively (P = .43). There was a somewhat greater
incidence of significant late morbidity in the RT-alone group (12% vs.
6%; P = .08).

Improved Treatment for Cervical Cancer
— Concurrent Chemotherapy and Radiotherapy
Thomas, G. M. (1999). Improved Treatment for Cervical Cancer ? Concurrent Chemotherapy and Radiotherapy. New
England Journal of Medicine, 340(15), 1198–1200. https://doi.org/10.1056/NEJM199904153401509

Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer:
a systematic review and meta-analysis of individual patient data from 18
randomized trials.
Reducing Uncertainties About the Effects of Chemoradiotherapy for Cervical Cancer: A Systematic Review and Meta-Analysis of Individual Patient Data
From 18 Randomized Trials. J Clin Oncol 26:5802-5812. © 2008 by American Society of Clinical Oncology

Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a
systematic review and meta-analysis of individual patient data from 18 randomized trials.
From 18 Randomized Trials. J Clin Oncol 26:5802-5812. © 2008 by American Society of Clinical Oncology

Stage Absolute5-yrsurvivalbenefit
Ib-IIa 10%
IIb 7%
III-IVa 3%
Reducinguncertainties about the effects of
chemoradiotherapyfor cervical cancer: asystematic review
and meta-analysis of individual patient data from 18
randomizedtrials.
From 18 Randomized Trials. Journal of Cl

New “standard-of-care” in stage IB2-
IVA is concurrent Cisplatin and RT

Stage IIB-IVA
squamous
cervical cancer
KPS >60%
Concurrent Cisplatin and
intracavitary RT
Endpoints
6-mo and 12-mo DCR (disease-control rate)
Is neo-adjuvant chemotherapy a better
option for management of cervical cancer
patients of rural India?
Dastidar, G.A., Gupta, P., Basu,B., Basu,A., Shah,J.K., & Seal,S.L.(2016). Is neo-adjuvant chemotherapy abetter option for management of cervical cancer patients of rural India?
Indian Journal of Cancer, 53(1), 56–9. https://doi.org/10.4103/0019-509X.180826
Rural-based
Urban-based
Neoadjuvant CT (Cisplatin +
Vincristine + Bleomycin) x3
followed by RT and intracavitary
RT
n=200
n=390

Stage IB2
cervical cancer
PS 0-2
NACT (Vincristine + Cisplatin)
followed by RHPPL
Radical histerectomy and
pelvic/para-aortic lymph-node
dissection (RHPPL)
Endpoints
PFS and OS
GOG-141: Treatment of ("bulky") stage IB cervical cancer with or without neoadjuvant
vincristine and cisplatin prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy:
a phase III trial of the gynecologic oncology group.
Eddy, G.L., Bundy, B.N., Creasman,W. T., Spirtos, N. M., Mannel, R.S.,Hannigan, E.,& O?Connor, D. (2007). Treatment of (?bulky?) stage IBcervical cancer with or without neoadjuvant
vincristine and cisplatin prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy: Aphase III trial of the gynecologic oncology group. Gynecologic Oncology, 106(2), 362–369.
https://doi.org/10.1016/j.ygyno.2007.04.007
n=291
Closed due to low accrual

Stage IB2, IIA2, IIB
squamous cervical cancer
By MRI
20-70
PS 0 or 1
Neoadjuvant CT (BOMP: Cisplatin
+ Vincristine + Mitomycin +
Bleomycin) x3, followed by Radical
Surgery (NACT-RS)
Radical surgery (RS)
Phase III randomised controlled trial of neoadjuvant chemotherapy plus radicalsurgery vs radical
surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial
(JCOG 0102)
n=134
Endpoint
OS
Post surgical RT if high risk pathology after RS
Pelvic lymph node metastasis,
parametrial involvement,
or deep stromal invasion (⩾2/3).
Katsumata, N., Yoshikawa, H., Kobayashi, H., Saito, T., Kuzuya, K., Nakanishi, T., …Japan Clinical Oncology Group. (2013). Phase III randomised controlled trial of neoadjuvant chemotherapy
plus
radical surgery vsradical surgery alone for stages IB2, IIA2, and IIB cervical cancer: aJapan Clinical Oncology Group trial (JCOG0102). British Journal of Cancer, 108(10), 1957–
63. https://doi.org/10.1038/bjc.2013.179

Phase III randomised controlled trial of neoadjuvant chemotherapy plus radicalsurgery vs radical
surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial
(JCOG 0102)
Katsumata, N., Yoshikawa, H., Kobayashi, H., Saito, T., Kuzuya, K., Nakanishi, T., …Japan Clinical Oncology Group. (2013). Phase III randomised controlled trial of neoadjuvant chemotherapy
plus
radical surgery vsradical surgery alone for stages IB2, IIA2, and IIB cervical cancer: aJapan Clinical Oncology Group trial (JCOG0102). British Journal of Cancer, 108(10), 1957–
63. https://doi.org/10.1038/bjc.2013.179

Stage IIB to IVA
cervical cancer
KPS ≥ 70%
Cisplatin + Gemcitabine (40 + 125 mg/m2,
q1w) + concurrent RT, followed by
intracavitary RT, followed by
Adjuvant CT with Cisplatin +
Gemcitabine (50 mg/m2 d1, 1000 mg/m2 d1 &
d8, q21d) x2 cycles
Cisplatin (40 mg/m2, q1w) + concurrent
RT, followed by intracavitary RT
Endpoint
PFS @ 3-yr
Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and
radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in
patients with stage IIB to IVA carcinoma of thecervix.
Dueñas-González, A., Zarb?, J.J., Patel, F.,Alcedo, J.C.,Beslija, S.,Casanova, L., …Orlando, M. (2011). PhaseIII, Open-Label, Randomized Study Comparing Concurrent Gemcitabine PlusCisplatin
and Radiation Followed by Adjuvant Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation in Patients With StageIIB to IVACarcinoma of the Cervix. Journal of Clinical Oncology,
29(13), 1678–1685. https://doi.org/10.1200/JCO.2009.25.9663
n=515
Weekly Cis
RT (external / intracavitary)
Standard of care (control)
Weekly Cis + Gem
Experimental arm
Adjuvant Cis + Gem

PFSa3 años:
74%
OSa3 años:
78.2%
PFSa3 años:
65%
OSa3 años:
69.1%
CisRT
Gemcitabina
CisRT
 Gemcitabine +CisRT:Gemcitabine
125 mg/m2 qW x6 +Cisplatio 40
mg/m2 qWx6(concurrent with RT).
Thenintracavitary RT,followed by 2
cyclesof adjuvant CTwithCisplatin+
Gemcitabine.
 CisRT:Cisplatin 40 mg/m2 qW x6
(concurrent with RT).Followedby
intracavitary RT
 HRpara PFS:0.68,
p=0.02
 HRpara OS:0.68,
p=0.022
LACC
GenCisRTenLACC
Dueñas-González,A. et al. JClinOncol27:18s, 2009 (suppl; abstr CRA5507) LemaTeachFiles®- 2009
n=515
n=259 n=256
Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin
and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin
and radiation in patients with stage IIB to IVA carcinoma of the cervix.
FIGOStagesIIB-IVACervicalcancer(Locally-advancedCervicalCancer–LACC)

Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin
and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin
and radiation in patients with stage IIB to IVA carcinoma of the cervix.
FIGOStagesIIB-IVACervicalcancer(Locally-advancedCervicalCancer–LACC)
Dueñas-González,A. et al. JClinOncol27:18s, 2009 (suppl; abstr CRA5507) LemaTeachFiles®- 2009

Phase III, open-label, randomized study comparing concurrent gemcitabine plus
cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus
concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the
cervix.
PFSat 3-yrmo(%)
OSat 3-yr(%)
74*
78*
46*
Grade3/4 toxicities(%)
65*86*
2
Treatment-related deaths(n)
n=515
Cisplatin+Gemcitabine+RT(external andintracavitary),
adjuvantCisplatin+ Gemcitabine
Cisplatin+RT(external and intracavitary),
69*
Dueñas-González, A., Zarb?, J.J., Patel, F.,Alcedo, J.C.,Beslija, S.,Casanova, L., …Orlando, M. (2011). PhaseIII, Open-Label, Randomized Study Comparing Concurrent Gemcitabine PlusCisplatinand
Radiation Followed by Adjuvant Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation in Patients With Stage IIB to IVA Carcinoma of the Cervix. Journal of Clinical Oncology,
29(13), 1678–1685. https://doi.org/10.1200/JCO.2009.25.9663

Phase III, open-label, randomized study comparing concurrent gemcitabine plus
cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus
concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the
cervix.
PFSat 3-yrmo(%)
OSat 3-yr (HRwith 95%C.I.)
74*
0.68(0.49-0.95)
46*
Grade3/4 toxicities(%)
65*86*
2
Treatment-related deaths(n)
n=515
Cisplatin+Gemcitabine+RT(external andintracavitary),
adjuvantCisplatin+ Gemcitabine
Cisplatin+RT(external and intracavitary),
Dueñas-González, A., Zarb?, J.J., Patel, F.,Alcedo, J.C.,Beslija, S.,Casanova, L., …Orlando, M. (2011). PhaseIII, Open-Label, Randomized Study Comparing Concurrent Gemcitabine PlusCisplatinand
Radiation Followed by Adjuvant Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation in Patients With Stage IIB to IVA Carcinoma of the Cervix. Journal of Clinical Oncology,
29(13), 1678–1685. https://doi.org/10.1200/JCO.2009.25.9663

Stage IB1 & node positive, IB2, IIA,
IIB, IIIB, or IVA disease
cervical cancer
PS 0-2
Adequate organ function Cisplatin (40 mg/m2, q1w) + concurrent
RT, followed by intracavitary RT
Endpoint
OS
OUTBACK: Cisplatin and Radiation Therapy With or Without Carboplatin and
Paclitaxel
in Patients With Locally Advanced Cervical Cancer
clinicaltrials.gov - NCT01414608 (Moore K,NRG)
Ongoing
Weekly Cis
Standard of care (control)
Experimental arm
Adjuvant Pacl + Carbo
Cisplatin (40 mg/m2, q1w) + concurrent
RT, followed by intracavitary RT,
followed by Pacl + Carbo q3w
x4
Weekly Cis

Neoadjuvant or Adjuvant
chemotherapy are NOT current
standards-of-care in LACC, but
the issue is far from settled.

Trialsinthe metastatic,persistent/recurrentdisease
Systemictherapy is often the onlyoption
 Cisplatin, introduced in the 80’soffered
modest short-term control inadvanced
cervical cancer…

Coleman RL.TheGynecologicOncologyGroup'srole in the treatment of recurrent
cervix cancer:Currentclinicaltrials. GynecologicOncology,Volume 110, Issue3,
Supplement 2, September2008, PagesS77-S80
Earlytrials in metastatic cervicalcancer
Trials
• GOG43(1987)
• GOG64(1989)
• GOG77(1989)
• GOG110(1997)
• GOG149(2002)
Research(C=Cisplatin)
• C:50 mg/m2 vs100 mg/m2
• C:Short vslong infusion
• CvsC+Ifosfamide(C/Ifo)
• C/Ifo vsC/Ifo/Bleomycin

Coleman RL.TheGynecologicOncologyGroup'srole in the treatment of recurrent
cervix cancer:Currentclinicaltrials. GynecologicOncology,Volume 110, Issue3,
Supplement 2, September2008, PagesS77-S80
Earlytrials in metastatic cervicalcancer
Trials
• GOG43(1987)
• GOG64(1989)
• GOG77(1989)
• GOG110(1997)
• GOG149(2002)
Summaryresults
• Low-dose Cisplatin (50 mg/m2)
• ORR:21%
• Median OS:7.1mo
• Carboplatin oirinotecán
•
•
ORR:15%
Median OS:6.2mo
•
•
High-doseCisplatin improves ORRbut not OS
Cisplatin plus Ifosfamide andBleomycin
• ORR:31%
• OS:8.5mo

Paclitaxel at an IV dose of 135
mg/m2 as a 24-hour infusion
followed immediately by cisplatin at a
dose of 50 mg/m2
cisplatin IV dose of 50 mg/m2
Stage IVB, recurrent, or persistent
disease that was not amenable to
curative treatment with surgery or
radiation therapy
PS 0-2
Endpoints
Response-rate, PFS or OS
GOG-169: Phase III study of cisplatin with or without paclitaxel in stage IVB,recurrent, or
persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study.
n=280
Moore, D. H., Blessing,J.A., McQuellon, R.P., Thaler, H. T., Cella, D., Benda, J., …Rocereto, T.F.(2004). PhaseIII Study of Cisplatin With or Without Paclitaxel in StageIVB, Recurrent, or
Persistent
Squamous Cell Carcinoma of the Cervix: AGynecologic Oncology Group Study. Journal of Clinical Oncology, 22(15), 3113–3119. https://doi.org/10.1200/JCO.2004.04.170

GOG-169: Phase III study of cisplatin with or without paclitaxel in stage IVB,
recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic
oncology group study.
ORR(%)
median PFS(mo)
36*
4.8*
2.8*
8.8
median OS(mo)
Paclitaxel +Cisplatin
Cisplatin
19*
9.7
n=280
Persistent

ORR(%)
median PFS(mo)
36*
4.8*
2.8*
8.8
median OS(mo)
Paclitaxel +Cisplatin
Cisplatin
19*
9.7
n=280
Persistent
GOG-169: Phase III study of cisplatin with or without paclitaxel in stage IVB,
recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic
oncology group study.

Cisplatin 50 mg/m(2) every 3 weeks
(CPT)
Cisplatin 50 mg/m(2) day 1 plus
topotecan 0.75 mg/m(2) days 1 to
3 every 3 weeks (CT)
radiation therapy
PS 0-2
Endpoint
OS
GOG-179: Randomized phase III trial of cisplatin with or without topotecan in
carcinoma of the uterine cervix: a Gynecologic Oncology Group Study.
Persistent Squamous Cell Carcinoma of the Cervix: AGynecologic Oncology Group Study. Journal of Clinical Oncology, 22(15), 3113–3119. https://doi.org/10.1200/JCO.2004.04.170
n=294
median PFS(mo)
27*
4.6*
2.9*
6.5*
Topetecan+Cisplatin
Cisplatin
13*
9.4*
n=294
median OS(mo) ORR(%)

GOG-179: Randomized phase III trial of cisplatin with or without topotecanin
carcinoma of the uterine cervix: a Gynecologic Oncology GroupStudy.
Long, H. J.,Bundy, B.N., Grendys, E.C.,Benda, J.A., McMeekin, D. S.,Sorosky, J., …Gynecologic Oncology Group Study. (2005). Randomized PhaseIII Trial of Cisplatin With or Without Topotecan
in Carcinoma of the Uterine Cervix: AGynecologic Oncology Group Study. Journal of Clinical Oncology, 23(21), 4626–4633.https://doi.org/10.1200/JCO.2005.10.021

GOG-204: Phase III trial of four cisplatin-containing doublet combinations in stage IVB,
recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study.
Cisplatin + Gemcitabine
Cisplatin + Vinorelbine
radiation therapy
Measurable disease
PS 0-1
Endpoint
OS
n=513
Cisplatin + Topotecan
Cisplatin + Paclitaxel
Monk, B.J.,Sill,M. W., McMeekin, D. S.,Cohn, D. E.,Ramondetta, L.M., Boardman, C.H., …Cella, D. (2009). PhaseIII Trial of Four Cisplatin-Containing Doublet Combinations in Stage IVB,
Recurrent,
or Persistent Cervical Carcinoma: AGynecologic Oncology Group Study. Journal of Clinical Oncology, 27(28), 4649–4655.https://doi.org/10.1200/JCO.2009.21.8909

Recurrent,

Cisplatin + non-paclitaxel (either
vinorelbine, gemcitabine or
topotecan)
Cisplatin + Paclitaxel
radiation therapy
Measurable disease
PS 0-1
Endpoint
OS
n=513
Recurrent,

GOG-204: Phase III trial of four cisplatin-containing doublet combinations in stageIVB,
recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Groupstudy.
ORR(%)
29
median PFS(mo)
5.8*
3.98-4.7*
10.1-10.3
median OS(mo)
Cisplatin+ Paclitaxel
Cisplatin+Non-paclitaxel doublet
23-26
12.9
n=513
Recurrent,

Paclitaxel PlusCarboplatin VersusPaclitaxel PlusCisplatinin Metastatic or Recurrent
CervicalCancer:TheOpen-LabelRandomizedPhaseIII Trial JCOG0505
Metastatic orrecurrent
cervical cáncer
≤1 prior platinum
No prior taxane
Paclitaxel plus carboplatin (TC;
paclitaxel 175 mg/m2 over 3 hours
and carboplatin area under curve 5
mg/mL/min on day 1, repeatedevery
3 weeks).
Paclitaxel plus cisplatin (TP;paclitaxel
135 mg/m2 over 24 hours on day 1
and cisplatin 50 mg/m2 on day 2,
repeated every 3weeks)
Non-inferiority OS(HR<1.29)
n =253
Kitagawa, R.,Katsumata, N., Shibata, T., Kamura,T., Kasamatsu,T., Nakanishi, T., …Yoshikawa, H.(2015). Paclitaxel PlusCarboplatin Versus
Paclitaxel PlusCisplatin in Metastatic or Recurrent CervicalCancer:TheOpen-Label Randomized PhaseIII Trial JCOG0505.Journal of
ClinicalOncology : Official Journal of the American Society of ClinicalOncology, 33(19), 2129–35.
https://doi.org/10.1200/JCO.2014.58.4391

Paclitaxel PlusCarboplatin VersusPaclitaxel PlusCisplatin in Metastatic or Recurrent Cervical
Cancer:TheOpen-Label Randomized PhaseIII Trial JCOG0505
Kitagawa, R.,Katsumata, N., Shibata, T., Kamura,T., Kasamatsu,T., Nakanishi, T., …Yoshikawa, H.(2015). Paclitaxel PlusCarboplatin Versus
Paclitaxel PlusCisplatin in Metastatic or Recurrent CervicalCancer:TheOpen-Label Randomized PhaseIII Trial JCOG0505.Journal of
ClinicalOncology : Official Journal of the American Society of ClinicalOncology, 33(19), 2129–35.
https://doi.org/10.1200/JCO.2014.58.4391

In advanced cervical cancer
paclitaxel plus either carboplatin or
cisplatin is the chemotherapy of
choice

Angiogenesis in
Cervical Cancer

GOG-240: Improved survival with bevacizumab in advanced cervical cancer.
Carcinoma of the cervix
Primary stage IVB
Recurrent/Persistent
Measurable disease
GOG PS 0-1
No prior chemotherapy for recurrence
Paclitaxel + Cisplatin
Paclitaxel + Cisplatin +
Bevacizumab
Endpoint
OS
n=452
Paclitaxel + Topetean
Paclitaxel + Topetean +
BevacizumabStratification factors
Stage IVB vs recurrent/persistence
GOG PS
Prior cisplatin exposure as radio sensitizer
Tewari, K.S.,Sill, M. W., Long, H. J., Penson, R.T., Huang, H., Ramondetta, L.M., …Monk, B.J.(2014). Improved Survivalwith Bevacizumabin Advanced Cervical Cancer. New EnglandJournal
of
Medicine, 370(8), 734–743. https://doi.org/10.1056/NEJMoa1309748

Carcinoma of the cervix
Primary stage IVB
Recurrent/Persistent
Measurable disease
GOG PS 0-1
No prior chemotherapy for recurrence
Chemotherapy +
Bevacizumab
n=452
Chemotherapy
Endpoint
OS
Stratification factors
Stage IVB vs recurrent/persistence
GOG PS
Prior cisplatin exposure as radio sensitizer
Tewari, K.S.,Sill, M. W., Long, H. J., Penson, R.T., Huang, H., Ramondetta, L.M., …Monk, B.J.(2014). Improved Survivalwith Bevacizumabin Advanced Cervical Cancer. New EnglandJournal
of
Medicine, 370(8), 734–743. https://doi.org/10.1056/NEJMoa1309748

Tewari, K.S.,Sill, M. W., Long,H.J.,Penson,R.T.,Huang,H., Ramondetta, L.M., …Monk, B.J.(2014). Improved Survival with
Bevacizumabin AdvancedCervical Cancer.New EnglandJournal of Medicine, 370(8), 734–743.
https://doi.org/10.1056/NEJMoa1309748
ORR(%)
median PFS(mo)
48^
8.2*
5.9*
13.3*
median OS(mo)
Chemotherapy+Bevacizumab
Chemotherapy
36*17*
n=452
Bevacizumab increases toxicity:
Hypertension of grade 2 or higher (25% vs. 2%),
Thromboembolic events of grade 3 or higher (8% vs. 1%), and
Gastrointestinal fistulas of grade 3 or higher (3% vs. 0%).

In advanced cervical cancer
chemotherapy plus bevacizumab
improves outcomes, and should be
considered a standard-of-care

Progress in survival in cervical
cancer
4.5
9.0
13.5
18.0
1989 2005 2013
GOG-169
GOG-179
GOG-64
Cisplatin
Cisplatin doublets
(Paclitaxel or Topetecan)
GOG-240
Chemotherapy +
Bevacizumab
medianOS(mo)
Year
Adding bevacizumab to chemotherapy improves survival

Systemictherapy in cervicalcancer
Atthe beginning
Only surgery and RTavailable
Today
Chemotherapy+
Bevacizumabin advanced
disease
Cisplatin in
advanced
disease in
earlytrials
Cisplatin+
RTin locally-
advanced
disease
Cisplatin+
Paclitaxelin
advanced
disease
Cisplatin+
Topotecan
andother
doubletsin
advanced
disease
Unresolved
Neoadjuvant and adjuvant chemotherapy in locally-advanceddisease
Immunotherapy andtargeted therapy in advanceddisease

Cis + Pac + Bev
(n=115)
Cis + Pac
(n=114)
Events, n (%)
Median OS, mos
69 (60.5)
14.3
67 (58.3)
17.5
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 12 3624
ProportionSurviving
RR, %
HR=0.68 (95% CI, 0.48-0.97)
P=0.0348
45 (CR, n=9) 50 (CR, n=17)
2-sided P=0.5090
GOG 240 – Bevacizumab Objective
Cisplatin + Paclitaxel Cohort N=229
Months on Study
Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG,FACS

Progress in Survival in Advanced and Recurrent Cervical Cancer
0.
4.5
9.
13.5
18.
1989 1997 2002 2004 2005 2009 2013
•GOG 149 Cisplatin + Ifosfamide + Bleomycin
 
•GOG 169 Cisplatin + Palitaxel
•GOG 179 Cisplatin + Topotecn
 
Months
Year
GOG 64 Cisplatin

• GOG 110 Cisplatin + Ifosfamide


GOG 240 Cisplatin + Palcitaxel + Bevacizumab

Adding Bevacizumab to Chemotherapy Improves Survival

83
Alexandrov et al., Nature 2013
Schumacher et al, Science 2015
Neoantigen Load and Tumor Types:
Possible use as a biomarker of activity for IO agent

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