1. Pierluigi Benedetti Panici,
LACC (Locally Advanced Cervical Cancer) : AN INTEGRATED APPROACH “Primary Treatment”
Pierluigi Benedetti Panici,
Innocenza Palaia

2. Epidemiology
Circa new cases worldwide. 80% developing countries
New Cases: about USA, 2200 Italy, Japan, 3200 UK, Europe (13.4/ ), European Union (11.3), etc

3. CERVICAL CANCER SURVIVAL
STAGE DISTRIBUTION
7th edition of the AJCC staging manual 2010

4. REPRESENT 70% OF ALL STAGES
LACC: IB2-IVA
REPRESENT 70% OF ALL STAGES
Wiebe, Int J Gyn Obst 2012

5. 5-Year Observed Survival Rate
CERVICAL CANCER SURVIVAL
Stage
5-Year  Observed Survival Rate I
80-93% II
58-63%
III
32-35% IV
15-16%
7th edition of the AJCC staging manual 2010

6. Surgery Radical pelvic surgery: excessive morbidity
History of radical abdominal hysterectomy
AW Freund 1878
TAH + bulky nodes
JG Clark 1895
Radical abdominal surgery
E Wertheim
Radical abdominal hyst + selective LA
Hidekazu Okabayashi 1921
Nerve sparing hyst
Victor Bonney 1935
Radical Hyst + systematic LA
J Meigs 1944
Radical abd hyst + routine LA
R Telinde 1950
Modified RAH
A Brunswig 1964
Pelvic exenteration
Piver-Rutledge 1974
Classification
Querleu Morrow 2008
Radical pelvic surgery: excessive morbidity

7. RADIOTHERAPY Discovery X-Ray 1895
1903 Marie and Pierre Curie, Becquerel
Treatment of choice first half 20 century (1920ies radiotherapy as oncologic revolution)
Some problems with radioprotection
Brachitherapy 1940

8. SURGEONS AND RADIOTHERAPISTS IMPROVED TECHNIQUES OVER YEARS
GOALS: SURVIVAL, TOXICITY, AVOID UNNECESSARY TREATMENT

9. Cervical cancer is a chemosensitive tumor

10. NACT 1983

11. Stage IB2-IIIB RS RT CT-RT NACT + RS CT-RT plus RS NACT + RT
LACC: TREATMENT OPTIONS
Stage IB2-IIIB RS RT
CT-RT
NACT + RS
CT-RT plus RS
NACT + RT

12. CTRT e NACT…where we are?
CTRT vs RT alone
4580 pts, 19 trials
OS HR 0.71, p<0.0001; absolute benefit 12%;
PFS HR 0.61; p<0.0001,absolute benefit 16%
NACT+RT vs RT alone*
2074 pts, 18 trials
Not significant OS and PFS
NACT+RS vs RT alone
872 pts, 5 RCT
HR 0.65 (p= ) favouring NACT,
14% gain in 5yOS, from 50 to 64%)
NACT +RS vs RS
1078 pts, 6 RCT
OS (HR 0.77, 95% (CI) , P = 0.02)
PFS (HR 0.75, 95% CI , P = 0.008) significantly improved with NACT
significant decrease in adverse pathological findings *
NCCCMC Eur J Cancer 2003; Green J, Lancet 2001; Rydzewska L, Cochrane Coll 2012

13. CHEMORADIATION + BRACHITHERAPY
STANDARD TREATMENT FOR LACC:
CHEMORADIATION + BRACHITHERAPY
EXTERNAL BEAM
pelvic
Radiation (40 to 60 Gy)
NCI Announcement 1999
I.V. CISPLATIN CHEMOTHERAPY
Cisplatin 40mg/m2 (Max dose 70mg)
IV q wk during RT (6wks)
BRACHYTHERAPY
(8,000 to 8,500 cGy to Point A)
5yOS
RT= 47%-75%;
CTRT= 67%-87%

17. Open issues CTRT Adjuvant treatment (Chemo, surgery)
Treatment of nodal metastasis
Treatment of relapse
Low resourches
Missing data on long term toxicity and QoL

18. Management of CC: MAIN TREATMENT Multimodality Approach
Gold standard
Good alternative
Experimental
Early stages
Surgery
(various degrees of tailoring)
(OS 80-90%) RT
- NACT+ surgery (various degree of tailoring)
- Conservative surgery
Locally advanced stages
Concomitant CT-RT
*(5 yOS= 66% (60-85%),
5y PFS= 58% (60-80%), 35% recurrent, 22.3% locoregional failures)
NACT+RS
- CTRT+RS
- NACT+CTRT
Metastatic disease
Individualized treatment
*MRC meta-analysis, JCO 2008
** Landoni et al, Lancet 1997 18

20. …why chemo-surgery is a good alternative…

21. NACT+RS 30 studies (22 phase II, 8 phase III) 1760 pts Ib2-IIIb
28/30 platinum based
2-3 cycles
ORR (CP,PR,SD)= 84%
90% operated
Type III + Pe LY. (AO in 5.6%)
Median PFS 67.5%
Median OS 70.7%
Relapse: 60% locoregional, 40% disseminated
Osman M, Oncol Rev 2014

22. + NACT+RS= PROS NACT SURGERY debulking effect and tumor size reduction
improve surgical outcomes
permit activity against micrometastasis
Reduce adjuvant (?)
SURGERY
Emotional satisfaction that the tumor has been removed
Ovarian preservation
Complications easier to redress
Pathological study of the specimen (prognostic factor, biomolecular)
Easier management of salvage therapy (RT) +

23. NACT+RS= CONS
NACT+ RS= small studies, possibility of adjuvant, different agents
CTRT is more feasible in elderly, obese and pts with comorbidity

24. AIMS: SURVIVAL DATA, TOXICITY, QOL
EORTC 55994
Randomized Phase III Study Of Neoadjuvant Chemotherapy Followed By Surgery Vs. Concomitant Radiotherapy And Chemotherapy In FIGO Ib2, IIa>4 cm or IIb Cervical Cancer R A N D O M
NACT+SURGERY
CISPLATIN BASED CHEMOTHERAPY
Min. total dose of 225 mg/mq
Piver III-V within 6 weeks
Adjuvant RT in case of N+, Parametria +
ONGOING
Not recruiting
CERVICAL CARCINOMA
FIGO STAGE IB2-IIB
CHEMO-RADIOTHERAPY
CDDP 40 mg/mq (6 weeks) + EBRT gy + brachitherapy
RS allowed not recommended
AIMS: SURVIVAL DATA, TOXICITY, QOL

25. …which agents…

26. 219 pts, median FU 43 mos 154 pts,median FU 43 mos
TIP=106
IP=113
Completed treatment
94%
90%
Reduction or delay
35%
18%
Grade 3-4 hem tox
Toxic death
59% 1
41% 3 OR
48%
23%
Deaths
25%
34%
Recurrence
26%
27.8%
154 pts,median FU 43 mos
TIP =74
TP=80
Completion treatment
97%
96%
Reduction or delay
22% 5%
Grade 3-4 hematol toxicity
78%
29%
Not operated 2 5
Optimal RR (CR+PR1)
Ib2
IIb
43%
53%
27%
25%
24%
5yPFS
5yOS
71%
64%
72%
Fase II randomizzata: non è possibile esprimere conclusioni definitive sul vantaggio in termini di sopravvivenza

27. Agents Eur J Cancer 1998 130 Ib2-III PTS N° PTS FIGO STAGE
Op rate %
CR= 10%, PR= 67% SD 19% PD 4%
RR cumulative: about 77%
PTS N°
PTS FIGO STAGE
NACT SCHEDULE
Ob Gyn 1988 33
IB-IIIB
CIS+BLEO+MTX
Cancer 1991 75
Gynecol Oncol 1996 42
Ib2-IIIb (adenok)
CBM, CB, CE
Eur J Cancer 1998
130
Ib2-III
CDDP/BLEO/MTX
JCO 2002
210
IB2-IIIB
CDDP-BASED
Ann surg oncol 2007 18
IVa
CDDP/Pacl
Gynecol Oncol 2011 46
CIS/Topo
Oncology 2015 22
CDDP
+TXL DD

28. Cisplatin Dose intensity
NACT+RT vs RT alone
2074 pts, 18 trials
Not significant OS and PFS
NCCCMC Eur J Cancer 2003; Green J, Lancet 2001; Rydzewska L, Cochrane Coll 2012

29. Impact of CC in QoL
“Cervical cancer survivors and short- survival cancer survivors reported the worst mental health related quality of life”
Cancer Epidemiol, Biomark & Prev 2012

30. Incidence: 38.4% in women <45y

31. GYNECOL ONCOL 2014

32. 24-88% in different series
38% in this study
It is not looked at specifically or is addressed
retrospectively, and therefore, the data may be
incomplete. Few studies have gathered the data prospectively.

33. Women after PRT report more physical, social, and sexual symptoms
Women after PRT report more physical, social, and sexual symptoms. These results can be well used by physicians to inform their patients about treatment-related morbidity.
Int J Gynecol Cancer 2017

34. 76% 9%

36. Our contribution in improvement QoL Tailoring parametrectomy

38. Type B vs Type C Radical Hysterectomy after neoadjuvant chemotherapy in locally advanced cervical carcinoma: a propensity-matched analysis.
Benedetti Panici P. Ann Surg Oncol 2015

41. Thanks to Prof. Stefano Greggi (SIOG 2015)

42. …future directions…

43. HUMAN PAPILLOMAVIRUS

44. NEOANGIOGENESIS E

46. THANK YOU LACC: AN INTEGRATED APPROACH CONCLUSION
The choice for primary treatment depends on patient characteristics (age, BMI, comorbidity), treatment side effects, preferences of the physician and patient, and resourches.
Multimodality approach is crucial.
Considering QoL, mandatory.
THANK YOU

47. Grazie per l’attenzione

48. NACT+RS Toxicity Chemotherapy toxicity: mild to moderate (transient)
Surgical sequelae:
- bladder dysfunction up to 76% in type III
- sexual dysfunction
- edema, etc
Cancer, 2004
Type of complication
No of pts (n= 610)
Wound
6.8%
Intestinal
5.2%
Urinary
20.2%
DVT
Lymphocysts
2.9%
Pulmonary
3.6%

49. EORTC 55994 PRELIMINARY DATA IGCS LISBONA 2016 NACT+SURGERY
314 PATIENT
CHEMO-RADIOTHERAPY
312 PATIENT
Patient characteristics
527(84.2%)SQUAMOUS CELL CARCINOMA
93(14.8%) ADENOSQUAMOUS CELL CARCINOMA
-168(26.8%) FIGO Ib2
-93(14.9%) FIGO IIA>4cm
-357(57%) FIGO IIB
dati preliminari PRESENTATI A IGCS LISBONA 2016
IGCS LISBONA 2016

50. Ongoing Phase III studies comparing NACT+RS vs CTRT in LACC
EORTC 55994
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE 686
Estimated Completion Date July 2019
Primary Completion Date July 2014   (final data collection date for primary outcome measure)
NACT CERVIX TATA MemoriaL Hospital
First Received Date  ICMJE September 11, 2005
Last Updated Date November 26, 2014
Start Date  ICMJE September 2003
Estimated Primary Completion Date December 2017   (final data collection date for primary outcome measure)
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE 730
Estimated Completion Date December 2017
TGOC phase III (Thailandia)
Estimated enrollment: 824
Study start date : June 2009
Estimated study completition date: June 2018
Estimated primary completition date: september 2013 (final data collection date for primary outcome measure)
NACOPRAD Charite University, Berlin, Germany
First Received Date  ICMJE February 11, 2015
Last Updated Date April 20, 2015
Start Date  ICMJE October 2015
Estimated Primary Completion Date October 2020   (final data collection date for primary outcome measure)
Not yet recruiting
Estimated Enrollment  ICMJE 534
Estimated Completion Date October 2025

51. WE ARE STILL WAITING FOR SURVIVAL
EORTC 55994
WAITING FOR FINAL RESULTS WITH CTRT LONG TERM TOXICITY
WE ARE STILL WAITING FOR SURVIVAL

52. Patients characteristics Cancer characteristics
Resources
Patients characteristics
Cancer characteristics
Skills and Institutions
Costs*:
RT equipment= E
Cost per treatment RT : E
3 CT cycles: E
Radical surgery= 6000 E
*Fonti: A.i.r.o. (Associazione italiana di radioterapia oncologica)
A.I.A.N., Associazione italiana per l’assistenza ai malati neoplastici

53. (LOW DOSE RT, NO BRACHI, BOOSTS)
CTRT + RS
(LOW DOSE RT, NO BRACHI, BOOSTS)
---Analysis of 381 pts (Jan 1996-July 2012)
---ROMA-2* prospective on 105 pts (Jan 2007-May 2012)
71.3% pathological complete/microscopic response
26% any grade of complication (16.6% >grade2)
Survival comparable to CTRT:
5y DFS 76%, 5y OS 80%
*Improvement in RR: 96% clinical response after CTRT + CBs (50% pCR, microCR 32%)
Legge Gyn Oncol 2015, Ferrandina Ann Surg Oncol 2014
Int J Rad Oncol 2014, Gynecol Oncol 2010

54. concl CTRT simile NACT+RS in Ib2-Iib III stadi challenging
AN INTEGRATED APPROACH

55. CONCLUSIONS: CC therapy
Aims:
Prolong survival Avoid recurrence (local /distant) QoL
Consider: Patients and cancer characteristics Available Literature data Accessibility Resourches/Skills/Institution/philosophy Weight benefits/complications
Directions:
Conservative surgery Improvements in RT administration (dosage, etc)
Tailoring therapy

57. Surgery after Complete Response to CTRT:
yes or no?
Trial closed for poor accrual
No difference OS between surgery vs no surgery after CTRT
This study failed to demonstrate that RH after EBRT-CT is superior to standard BCT

59. …our experience…

60. Feb-1999: NCI issues clinical announcement on cervical cancer
EXTERNAL BEAM
pelvic
Radiation (40 to 60 Gy)
BRACHYTHERAPY
(8,000 to 8,500 cGy to Point A)
The benefit of chemoradiation for women with locally advanced cervical cancer rather than RT alone was demonstrated in a 2010 meta-analysis [7]. Compared with primary RT, the use of chemoradiation resulted in: ●
A reduction in the risk of death (hazard ratio [HR] 0.69, 95% CI ), which translated into a 10 percent absolute improvement in survival. The survival benefit associated with chemoradiation significantly decreased with increasing stage. For women with stage IB to IIA, IIB, and III to IVA cervical cancer, the five-year survival benefit was 10, 7, and 3 percent, respectively (p = 0.017).
A reduction in the risk of recurrence (HR 0.66, 95% CI ), which translated into a 13 percent absolute improvement in progression-free survival (PFS). There was no association between stage and disease-free survival reported.
A reduction in the risk of local recurrence (odds ratio [OR] 0.59, 95% CI ) and a trend towards a reduction in distant metastases (OR 0.81, 95% CI ). This reduction was seen in trials using both platinum-based and non-platinum-based regimens.
Higher rates of serious (grade 3/4) adverse events, including gastrointestinal toxicity (OR 1.98, 95% CI ).
I.V. CISPLATIN CHEMOTHERAPY
Cisplatin 40mg/m2 (Max dose 70mg)
IV q wk during RT (6wks)
reduction in risk of death (HR 0.69, 95% CI )
reduction in risk of local recurrence (OR 0.59, 95% CI )
trend in reduction of distant metastasis (OR 0.81, 95% CI )

61. CT-RT= 67-87%; RT= 47-74% FIGO Stages Pts in Arm Radiation regimen
Chemotherapy regimen
5y-OS
Whitney 1999
IIB-IVA
177
191
Pelvic EBRT/IC
CDDP-5FU
(Hydroxyurea)
67%
57%
Morris
1999
IB2-IVA
195
193
Pelvic and PA EBRT/IC
None
75%
63%
Rose 1999
173
176
Weekly CDDP
65%
47%
Peters 1999
IA2-IIA
127
116
87%
77%
Keys 1999
IB2
183
186
83%
74%
CT-RT= 67-87%; RT= 47-74%

62. Median survival months
Effects of Neoadjuvant Chemotherapy plus Radical Surgery as Front Line Treatment Strategy in Patients Affected by FIGO Stage III Cervical Cancer
52 FIGO stage III CC
2005 to 2015
RS was performed in 40 (76.9%)
Radical Operated
Median survival months
RS (N=40) 48
CT alone (N=3) 13
CTRT (N=9) 15
Not Radical Operated
Annals of Surgical Oncology 2016

63. Benedetti Panici P et al. JCO 2002
441 pts
14 Institutions
78% operated
10-15% survival advantage
Benedetti Panici P et al. JCO 2002

64. OS according to protocol
60.2% (95% CI, 51.8% to 68.6%) vs
46.8% (95% CI, 37.4% to 56.2%) (p=0.02)
PFS according to protocol
56.9% (95% CI, 48.5% to 65.3%) v 47.8%
(95% CI, 39.2% to 56.4%) (P .03)
SUBGROUP ANALYSIS: NO SIGNIFICANT FOR STAGE III