Ο ΡΟΛΟΣ ΤΗΣ ΑΚΤΙΝΟΘΕΡΑΠΕΙΑΣ ΣΤΟΝ ΠΡΩΙΜΟ ΚΑΡΚΙΝΟ ΤΟΥ ΤΡΑΧΗΛΟΥ ΤΗΣ ΜΗΤΡΑΣ

2 o Masterclass Γυναικολογικής Ογκολογίας 9-10 Ιουνίου 2017, Electra Metropolis, Αθήνα Ο ΡΟΛΟΣ ΤΗΣ ΑΚΤΙΝΟΘΕΡΑΠΕΙΑΣ ΣΤΟΝ ΠΡΩΙΜΟ ΚΑΡΚΙΝΟ ΤΟΥ ΤΡΑΧΗΛΟΥ ΤΗΣ ΜΗΤΡΑΣ A. Ι. ΔΗΜΟΠΟΥΛΟΣ ΔΙΕΥΘΥΝΤΗΣ ΚΛΙΝΙΚΗΣ ΑΚΤΙΝΟΘΕΡΑΠΕΥΤΙΚΗΣ ΟΓΚΟΛΟΓΙΑΣ Metropolitan Hospital ΑΝΑΠΛ. ΚΑΘΗΓΗΤΗΣ (VENIA DOCENTI) ΠΑΝ/ΜΙΟΥ ΒΙΕΝΝΗΣ ΑΥΣΤΡΙΑΣ FACULTY MEMBER EUROPEAN SOCIETY OF THERAPEUTIC RADIATION ONCOLOGY

2 o Masterclass Γυναικολογικής Ογκολογίας 9-10 Ιουνίου 2017, Αθήνα Review of Existing (important) Guidelines NCCN Guidelines V. 1.2014 ESMO Guidelines American Brachytherapy Society Guidelines Belgian National Practice Guidelines-KCE ACR Appropriateness Criteria Scottish Intercollegiate Guidelines Network - A National Clinical Guideline Malaisian National Guidelines Royal College of Radiologists Clinical Practice Guidelines Alberta Health Services Evidence Based Management Guidelines - Tata Memorial Hospital Best Cinical Practice Guidelines Greater Metropolitan Clinical Taskforce And many others (medical associations and societies etc.) Clear landscape Almost no changes over the last years

TREATMENT OF CERVICAL CANCER ACCORDING TO STAGE LOCALLY LIMITED DISEASE STAGE IA1 IA2

TREATMENT OF CERVICAL CANCER ACCORDING TO STAGE LOCALLY LIMITED DISEASE STAGE IA1 IA2 For stage IA1 with LVSI and for stage IA2 Radical Radiotherapy (pelvic RT + Brachytherapy) alternate option only if medically inoperable or patient is refusing surgery

TREATMENT OF CERVICAL CANCER ACCORDING TO STAGE LOCALLY LIMITED DISEASE STAGE IB - IIA

1 Is Radical Radiotherapy or Radical Hysterectomy better? Radical Radiotherapy versus Radical Hysterectomy

Radiotherapy characteristics: EBRT(18 MV) median TD 47 Gy (40-53 Gy); 1.8-2 Gy per fx BT LDR, median TD to point A 76 Gy (70-90 Gy) 64% of patients from surgery arm had adjuvant radiotherapy! * *Crude rates are given! Landoni et al 1997

* *Grade 2 - major symptoms requiring prolonged therapies or hospitalization for diagnosis and medical management Grade 3 - severe morbidity requiring invasive or surgical procedures Landoni et al 1997

20-year update of the Landoni trial Squamous cell CA Adeno CA Landoni et al 2017

Two studies based on SEER Data Two studies with small unequal arms Tumors <4cm significantly more in surgery arms Younger patients preferably treated with surgery Landoni et al 2017

2 Does adjuvant hysterectomy after radical radiotherapy improve the results? Radical Radiotherapy versus Radiotherapy and adjuvant Surgery

256 patients Stage IB tumor of 4 cm lymph node staging optional no paraaortic nodes OS and PFS not significantly different RT + adjuvant Hysterectomy is not superior to RT Keys et al 2003 - GOG 71

3 Neoadjuvant Radiochemotherapy better than Neoadjuvant Radiotherapy? Radiochemotherapy and Surgery versus Radiotherapy and Surgery

369 patients Stage IB, N0 with: Tumour >4 cm Negative lymph nodes Lymph node staging optional 183 RT +Cisplatin186 RT 3-y.PFS 78% 65%, p=0.001 3-y. survival 83% 74%, p=0.008 Keys et al 1999

4 Indications for Radiotherapy after surgery? Surgery versus Surgery and Radiotherapy

277 patients Stage IB, N0 with 2 of the risk factors: >1/3 stromal invasion LVI Tumour 4 cm HE + RADIOTHERAPY vs. HE + OBSERVATION 137 HE+RT vs 140 HE Recurrences 15% vs 28% p=0.008 Sedlis et al 1999 INTERMEDIATE RISK patients after Hysterectomy The addition of radiotherapy is required

277 patients Stage IB, N0 with 2 of the risk factors: >1/3 stromal invasion LVI Tumour 4 cm HE + RADIOTHERAPY vs. HE + OBSERVATION Morbidity Gr 3-4: 6.6% vs. 2.1% Rotman et al 2006 INTERMEDIATE RISK patients after Hysterectomy The addition of radiotherapy is required

Siegel et al. Cancer J Clin 2015 Barnholtz-Sloan et al. Cancer Causes Control 2009 Wang et al. Cancer 2010 Howe et al. Cancer 2006

5 Indications for Radiochemotherapy after surgery? Surgery plus Radiotherapy versus Surgery plus Radiochemotherapy

243 patients Stage IA2,IB, IIA with: Positive margins Positive lymph nodes Parametrial invasion HE + RADIOTHERAPY vs. HE + RADIOCHEMOTHERAPY HE + RCT HE + RT 3y PFS 87% 77% 3y OS 81% 71% (SS) Peters et al 2000 HIGH RISK patients after Hysterectomy The addition of radiochemotherapy is required

RTOG-0724 Lead Group: RTOG GOG-0263 Lead Group: GOG SWOG NSABP NCIC NCCTG GOG ECOG CALGB ACOSOG OTHER ONGOING STUDIES!!! POST-OP HIGH RISK CERVICAL OUTBACK CANCERS: TRIAL Phase MULTICENTRIC III Randomized PHASE Study III STUDY SWOG RTOG NSABP NCIC NCCTG ECOG CALGB ACOSOG of Concurrent Chemotherapy and Pelvic RT With or Without Adjuvant (Pacli + Carbo every 21 days x 4 cycles) Chemotherapy in High-Risk Patients with Early-Stage Cervical Carcinoma Following Radical Hysterectomy POST-OP INTERMEDIATE RISK CERVICAL CANCERS: Randomized Phase III Clinical Trial of Adjuvant Radiation Versus Chemo-radiation in Intermediate Risk, Stage I/IIA Cervical Cancer Treated with Initial Radical Hysterectomy and Pelvic LND dissection Recruiting Target: 400 Recruiting Target: 534 OUTBACK TRIAL - ONGOING

Image-Guided Adaptive Brachytherapy for Cervical cancer! Image Guided Brachytherapy clinical outcome?

CONCOMITANT RADIOCHEMOTHERAPY LINAC, 18 MV Pelvic RT EBRT 4 fields or IMRT Single dose= 1.8 Gy Overall dose= 45 Gy 1. Brachytherapy 2. Brachytherapy Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Brachytherapy Single dose= 7 Gy Overall dose= 28 Gy Cisplatin 40 mg/m 2 /week Treatment duration: 7 weeks

Image-Guided Adaptive Radiotherapy for Cervical Cancer Limitations of 2D X-ray based BT: Point A! External Beam Radiotherapy The first component of definitive cervical cancer treatment simple integration of 3D EBRT and Brachytherapy 45 Gy EBRT + 4 x 7 Gy BT = 84 Gy (EQD2)

Image-Guided Adaptive Radiotherapy for Cervical Cancer Limitations of 2D X-ray based BT: Point A! Brachytherapy The secondcomponent of definitive cervical cancer treatment simple integration of 3D EBRT and Brachytherapy 45 Gy EBRT + 4 x 7 Gy BT = 84 Gy (EQD2) B 84 Gy 60 Gy R GTV HR-CTV

Absolute Vol (cm³) Image-Guided Adaptive Brachytherapy for Cervical cancer What is happening during Radiotherapy course! Quantitative tumor regression EBRT: tumor regression 75% Brachytherapy: tumor regression 10% easy to predict 70 60 61,0 50 40 30 EBRT 20 10 16,3 10,5 BT 9,0 7,9 0 prior to therapy 1. brachytherapy 2. brachytherapy 3. brachytherapy 4. brachytherapy Dimopoulos et al. Strahlenther Onkol 2009

TUMOR REGRESSION WHAT IS HAPPENING DURING EBRT! 1 External Beam IMRT 1.8Gy x 25 = 45Gy

TUMOR REGRESSION WHAT IS HAPPENING DURING EBRT! Time (during EBRT treatment)

TUMOR REGRESSION WHAT IS HAPPENING DURING EBRT! Time (after the end of EBRT treatment)

TUMOR REGRESSION WHAT IS HAPPENING DURING BT! Time (during BT treatment)

Image-Guided Adaptive Brachytherapy: Clinical endpoint: local control! Time of diagnosis Local control B GTV R C Time of brachytherapy B 45 Gy EBRT + 4 x 7 Gy BT = 84 Gy (EQD2)60 Gy GTV R HR-CTV Abstract Book of the 6th International RGCON Conference on Cervica Cancer Delhi 31st March & 1st April; p13-21 - Pötter R, Dimopoulos J.

RESULTS TARGET (HR CTV) TOPOGRAPHY, HIGH DOSE AREA and RECURRENCE: n=141, 523 treatment plans / 608 fractions Diagnosis Diagnosis GTV HR CTV Brachytherapy B B B GTV DG GTV DG 84 Gy EQD2 R a 6 mths after treatment 6 mths after treatment 9 mths after treatment b R c C C d e f Dimopoulos et al. Int J Radiat Oncol Biol Phys 2009

Image-Guided Adaptive Brachytherapy for Cervical cancer! Relating Dose parameters to clinical outcome?

Image-Guided Adaptive Brachytherapy: RESULTS TARGET DVH-PARAMETERS! Local control and cut-off levels for D90 and D100 for the HR CTV n=141, 523 treatment plans / 608 fractions Subgroup Entire population 141 (2) >5cmDIAG 76 (2a) >5cmDIAG 2-5cmBT 45 (2b) >5cmDIAG >5cmBT 31 n Number (and %) of LRs above or below a cut-off D90 HR CTV D100 HR CTV < 87 Gy 87 Gy < 66 Gy 66 Gy 15/73 (20%) 3/68 (4%) 14/81 (17%) 4/60 (7%) 15/45 (33%) 1/31 (3%) 14/44 (32%) 2/32 (6%) 4/21 (19%) 1/24 (4%) 4/21 (19%) 1/24 (4%) 11/24 (46%) 0/7 10/23 (43%) 1/8 (13%) D90 for the HR CTV: cut-off 87 Gy EQD2 Local recurrences: 4% versus 20% D100 for the HR CTV: cut-off 66 Gy EQD2 Local recurrences: 7% versus 17% Dimopoulos et al. Int J Radiat Oncol Biol Phys 2009

Image-Guided Adaptive Brachytherapy: RESULTS TARGET DVH-PARAMETERS! HR CTV and probability for local tumour control n=141, 523 treatment plans / 608 fractions Conclusion: a significant dependence of local control on D100 and D90 for HR CTV was found. Tumour control rates of >90% can be expected at doses of >67Gy and 86Gy, respectively. Dimopoulos et al. Radiother Oncol 2009

Local control and cancer specific survival (1998-2003): TREATMENT PERIOD (-/+ IGABT) AND TUMOUR SIZE 18% 22% mean 81 Gy vs. 90 Gy in HR CTV Pötter R, Dimopoulos J, Georg P et al. Radioth Oncol 2007

%,G3/G4 GI and urinary morbidity Image-Guided Adaptive Brachytherapy for Cervical cancer - Clinical Endpoints! Late morbidity (LENT/SOMA) actuarial 8% (G3/G4 LENT/ SOMA 145 consecutive patients two Treatment periods: -learning: 1998-2000 -systematic application: 2001-2003 D2cm3 Bladder 95 Gy EQD2 Rectum 55 Gy EQD2 Sigmoid 62 Gy EQD2 GI+GU) G1, n G2, n 12 10 8 6 4 2 0 G3, n BLADDER 7 11 1 2 RECTUM/ SIGMOID 2 7 2 2 SMALL INTESTINE/COLON 5 0 0 0 VAGINA 78 36 5 0 10% 1 2% 1998-2000 2001-2003 ACTUARIAL OVERALL MORBIDITY RATE (G3 and G4) (GASTROINTESTINAL AND URINARY) at 3 years G4, n Pötter R, Dimopoulos J, Georg P et al. Radioth Oncol 2007

Image-Guided Adaptive Brachytherapy for Cervical cancer - Clinical Endpoints! Pötter R, Dimopoulos J, Georg P et al. Radiother&Oncol 2011

7ο Μετεκπαιδευτικό 2 o Masterclass Σεμινάριο Γυναικολογικής Κλινικής και Ερευνητικής Ογκολογίας 2017 Ογκολογίας 21-23 9-10 Ιανουαρίου Ιουνίου 2017, 2016, Electra Hilton, Metropolis, Αθήνα Αθήνα Castelnau-Marchand et al. Gynecol Oncol 2015

EMBRACE STUDY=OBSERVATIONAL STUDY Patient accrual>1300!!! Fat suppressed images How is the GTV defined? Inconsistencies in GTV delineation Grey-zones are not included

STAGE IA1-IIA STAGE IA1 WITH LVSI AND STAGE: IA2 RT ONLY IF MEDICALLY INOPERABLE OR PATIENT REFUSES SURGERY SURGERY VERSUS RADIOTHERAPY EQUAL, BUT 65% OF PATIENTS TREATED WITH SURGERY RECEIVE ADJUVANT RADIO(CHEMO)THERAPY SURGERY AFTER DEFINITIVE RADIOTHERAPY IS NOT IMPROVING OVERALL SURVIVAL COMPARED TO DEFINITIVE RADIOTHERAPY ALONE NEOADJUVANT RADIOCHEMOTHERAPY FOLLOWED BY SURGERY IS SUPERIOR TO NEOADJUVANT RADIOTHERAPY FOLLOWED BY SURGERY

STAGE IA1-IIA PATIENTS WITH 2 INTERMEDIATE RISK FACTORS AFTER SURGERY: i.e. >1/3 INVASION OF CERVICAL STROMA, LVI, TUMOR SIZE 4 cm SHOULD RECEIVE ADJUVANT RADIOTHERAPY PATIENTS WITH ONE HIGH RISK FACTORS AFTER SURGERY PARAMETRIAL INVASION, POSITIVE LYMPH NODES, POSITIVE MARGINS SHOULD RECEIVE ADJUVANT RADIOCHEMOTHERAPY IN THE RADICAL SETTING MR IMAGE GUIDED BRACHYTHERAPY IMPROVES SIGNIFICANTLY CLINICAL OUTCOME

TREATMENT OF CERVICAL CANCER ACCORDING TO STAGE LOCAL DISEASE STAGE IB IVA RADICAL RADIOTHERAPY RADICAL RADIOCHEMOTHERAPY

RESULTS TRADITIONAL RT TECHNIQUES Mean 5 year local control rates IB 90% IIA 83% IIB 60-87% Gerbaulet A, Pötter R, Haie-Meder C. Cervix Carcinoma. In: Gerbaulet A, Pötter R, Mazeron JJ, Meertens H, Van Limbergen E, eds. (2002) Α. Ι. ΔΗΜΟΠΟΥΛΟΣ Ο ΡΟΛΟΣ ΤΗΣ ΑΚΤΙΝΟΘΕΡΑΠΕΙΑΣ ΣΤΟΝ The ΠΡΩΙΜΟ GEC ESTRO Handbook ΚΑΡΚΙΝΟ of Brachytherapy. ΤΟΥ ΤΡΑΧΗΛΟΥ Brussels:ESTRO ΤΗΣ ΜΗΤΡΑΣ

RESULTS TRADITIONAL RT TECHNIQUES Mean 5 year local control rates distal IIB 77% IIIB 44-66% IVA 18-48% Gerbaulet A, Pötter R, Haie-Meder C. Cervix Carcinoma. In: Gerbaulet A, Pötter R, Mazeron JJ, Meertens H, Van Limbergen E, eds. (2002) Α. Ι. ΔΗΜΟΠΟΥΛΟΣ Ο ΡΟΛΟΣ ΤΗΣ ΑΚΤΙΝΟΘΕΡΑΠΕΙΑΣ ΣΤΟΝ The ΠΡΩΙΜΟ GEC ESTRO Handbook ΚΑΡΚΙΝΟ of Brachytherapy. ΤΟΥ ΤΡΑΧΗΛΟΥ Brussels:ESTRO ΤΗΣ ΜΗΤΡΑΣ

100% RESULTS TRADITIONAL RT TECHNIQUES 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% IB IIA IIB IIIB IVA Gerbaulet A, Pötter R, Haie-Meder C. Cervix Carcinoma. In: Gerbaulet A, Pötter R, Mazeron JJ, Meertens H, Van Limbergen E, eds. (2002) Α. Ι. ΔΗΜΟΠΟΥΛΟΣ Ο ΡΟΛΟΣ ΤΗΣ ΑΚΤΙΝΟΘΕΡΑΠΕΙΑΣ ΣΤΟΝ The ΠΡΩΙΜΟ GEC ESTRO Handbook ΚΑΡΚΙΝΟ of Brachytherapy. ΤΟΥ ΤΡΑΧΗΛΟΥ Brussels:ESTRO ΤΗΣ ΜΗΤΡΑΣ

RESULTS RADIOCHEMOTHERAPY Stage IB2-IVA American National Cancer Institute primary radiochemotherapy is the standard of care for locally advanced (stage IB2-IVA) cervical cancer Standard defined by 5 randomized Studies

RESULTS RADIOCHEMOTHERAPY

2 o Masterclass Γυναικολογικής Ογκολογίας 2017 9-10 Ιουνίου 2017, Electra Metropolis, Αθήνα AUTHOR RANDOMISATION ARMS STAGE LOCOREGIONAL Keys et al N Engl J Med. 1999 Whitney et al 3 YEAR RESULTS RADIOCHEMOTHERAPY RECURRENCE OVERALL SURVIVAL AND RECURRENCE AFTER CONCOMITANT CHEMOTHERAPY AND RADIOTHERAPY FOR CANCER OF UTERINE CERVIX: A SYSTEMATIC REVIEW AND RT + Cisplatin + HEMETA-ANALYSIS Bulky IB 9% 83% RT+ HE RT + Cis/5-FU SURVIVAL 21% RR 0.51 (95% CI) 3656 patients IIB,III, (19 studies) 24.9% 74% (p=0.008) RT + HU IVA 30.4% 57% J Clin Oncol. 1999 LOCAL RECURRENCE RATE WAS SIGNIFICANTLY REDUCED RR 0.79 (90% BY CHEMORADIATION CI) (p=0.018) OR 0.61, 95% CI 0.51-0.73, p< 0.0001 Rose et al RT + Cisplatin IIB,III, Not reported 65% N Engl J Med. 1999 RT + Cis/5-FU+HU IVA 65% RCHT RT RT + HU 47% OS 52% 40% (p=0.004) Morris et al RT + Cis/5-FU N Engl PFS RT (pelvis + paraaortal) J Med. 1999 Toxicity Grade 3-4 PetersHaematological al HE + RT + Cis/5-FU GastrointestinalHE + RT J Clin Oncol. 2000 Pearcey et al J Clin Oncol. 2002 RT+Cisplatin RT IB-IVA (~70% IB- IIB in each group) 63% 16% IA2,IB, 9% IIA 19% 35% RR 0.47 (95% CI) 5.5% 17% 47% 8% 4% 67% 75% 63% (p=0.004) 81% 71% (p=0.007) IB-IVA Not reported Green et al. Lancet 2001;358:781-86 69% 66% (p=0.42)

RESULTS RADIOCHEMOTHERAPY Phase III trials with concurrent chemo-radiotherapy in stage IB2-IVa CERVICAL CANCER: Dose of Cisplatin/m2 GOG 85 Cisplatin 50 mg day 1, 29 + FU GOG 120 Cisplatin 50 mg day 1, 29 + FU +HU GOG 120 Cisplatin 40 mg weekly GOG 123 Cisplatin 40 mg weekly SWOG8797/GOG 109 Cisplatin 70 mg day 1, 22 + FU RTOG 9001 Cisplatin 70 mg day 1, 22 + FU NCIC Cisplatin 40 mg, weekly

NCIC Trial: Median follow-up: 82 months Stage IB2 and IIA (5 cm in diameter), IIB, IIIB, IIIA, and IVA ( < 5cm if LN + ve) Randomization CT+RT (CDDP) 127 pts RT alone 126 pts OS 3 yrs 69% 66% 5 yrs 62% 58% HR 1.13 (95% CI 0.77 to 1.67) P=0.42 Approximately 53% of patients on the CRT regimen had decreases in their hemoglobin levels of 9 g/l or more. Conclusions: The best results are certainly achieved by careful attention to RT details, including dose and overall delivery time, the use of ICBT whenever possible, and probably the addition of concurrent CDDP CRT Pearcey et al JCO 2002

Reduction in the risk (1 - relative risk) of death from six CRT trials in cervix cancer Collectively, the six trials continue to support improvement in local control, PFS, and OS with concurrent cisplatin-based CRT Although the NCIC study alone fails to demonstrate significant differences all outcomes slightly favored cisplatin CRT Α. Ι. ΔΗΜΟΠΟΥΛΟΣ Ο ΡΟΛΟΣ ΤΗΣ ΑΚΤΙΝΟΘΕΡΑΠΕΙΑΣ ΣΤΟΝ ΠΡΩΙΜΟ Editorial ΚΑΡΚΙΝΟ : Rose, ΤΟΥ ΤΡΑΧΗΛΟΥ P. G. et ΤΗΣ al ΜΗΤΡΑΣ JCO 2002

Cochrane Collaborative Group (19 Trials) (4580 patients) Green JA et al Lancet 2001 19 RCTs between 1981 and 2000 Increase in OS by 12% & RFS by 16% (p=0.0001) Greater benefit in patients in stages IB2 and IIB Decrease in local and systemic recurrence (p=0.0001) Update in July 2005: 21 trials and 4921 pts Similar findings (OS:10%; PFS: 13% ) Test for Heterogeneity : Positive No data on late toxicities Cochrane Database Syst Rev. 2005

Canadian Group (9 Trials) - 4 year survival data - Meta-analysis Cisplatin based Concomitant Chemo-radiation Significant improvement in Overall Survival - Advanced Stages (only 30% tumors) - Bulky IB tumors (prior to surgery) - risk early disease (post-surgery) Toxicities Acute Grade 3/4 Hematological and GI significantly higher : all short lived - 2 deaths due to the toxicities - No significant late toxicities seen Lukka et al. Clinical Oncology 2002

Uncertainties about the effects of chemoradiotherapy THE CHEMORADIATION FOR CERVICAL CANCER META-ANALYSIS COLLABORATION- (CCCMAC) MEDICAL RESEARCH COUNCIL CLINICAL TRIALS UNIT- UK JCO 2008

REDUCING UNCERTAINTIES ABOUT CHEMORADIATION: SYSTEMATIC REVIEW AND META-ANALYSIS Adjuvant CT after CRT needs to be explored further There was however the suggestion of a decreasing relative effect of chemoradiation on survival with increasing tumor stage, with estimated absolute survival benefits of 10% (stage Ia-IIa), 7% (stage IIb) and 3% (stage III-IVa) at 5-years JCO 2008

REDUCING UNCERTAINTIES ABOUT CHEMORADIATION:STAGE IIIB Not powered enough to show difference in OS Recent study for stage IIIB patients confirms the decreasing relative effect of chemo-radiation on survival with increasing tumor stage Another study: Srivastava et al. Asia Pac J Clin Oncol 2013 shows no benefit for advanced stages by the addition of Cisplatin JCO 2014

Concomitant Chemo-Radiation in Advanced Stage Carcinoma Cervix (CRACx)(2014) August 2003 to Aug. 2011 = 850 pts Randomized only patients with IIIB SCC Follow-up: Median: 36 months (mean : 39 range : 12-76) 2011 RT ALONE (425 pts) CT + RT (425 pts) NED 225 245 Recurrences 187 171 Loco - regional Recurrence Distant Mets LR Distant Persistent Disease 62 62 39 24 60 53 27 29 Died due to Disease 187 169 (2 pts New Primary) Died due to Rx Complications 01 (Unknown) 02 Died of other causes / UK 44 27 Lost to follow-up 63 69 Late sequelae Rectal Gr 2 Rectal Gr 3 10 (2%) 8 (1.5%) 15 (3%) 4 (0.8%) Acute Haematological and GI toxicities : Higher with concomitant CRT Disease outcome: Better in favour of Chemoradiation Completion of accrual and final outcome analysis : Awaited Mahantshetty et al; ESTRO -31 2012 FINAL ANALYSIS: Ongoing

MRC IPD Meta-analysis JCO Dec 2008 Green Meta-analysis Update Cochrane Database Syst Rev 05 Lukka Meta-analysis, Clin Oncol 02 CRITICAL REVIEW OF EVIDENCE Heterogenous patient data Suboptimal Radiotherapy Schedules Used Non-uniform use of CT drugs and Sequencing QOL issues : Unknown Sparse literature from developing countries Green Meta-analysis, The Lancet 01 Pearcey, Proc ASCO 00 [abst] NCI Clinical Announcement 1999 Rose, Keys, Morris, Peters, Whitney Wong, Gynecol Oncol 89

ADENO AND ADENOSQUAMOUS CELL CARCINOMA RETROSPECTIVE ANALYSIS OF GOG 85, 120, 123, 165 and 191!!! WITHOUT CISPLATIN WITH CISPLATIN NULLIFICATION OF POOR OUTCOME FOR ADENO AND ADENOSQUAMOUS CARCINOMAS WITH THE ADDITION OF CDDP TO RADIATION!!! Rose et al. Gynecol Oncol 2014

4 Arms, 926 patients: THE ISSUE OF ALTERNATE CHEMOTHERAPY!!! Arm 1: RT Arm 2: RT + adjuvant CHT Arm 3: RT+ concomitant CHT Arm 4: RT + concomitant CHT + adjuvant CHT Conc. CHT = 2 x (MMC + oral 5-FU (15d)) Adj. CHT = 3 x oral 5-FU (4 weeks) Α. Ι. ΔΗΜΟΠΟΥΛΟΣ Ο ΡΟΛΟΣ ΤΗΣ ΑΚΤΙΝΟΘΕΡΑΠΕΙΑΣ ΣΤΟΝ ΠΡΩΙΜΟ ΚΑΡΚΙΝΟ ΤΟΥ Lorvidhaya ΤΡΑΧΗΛΟΥ ΤΗΣ et ΜΗΤΡΑΣ al

THE ISSUE OF NEOADJUVANT CHEMOTHERAPY!!! THE MOST IMPORTANT COMPARISON IS MISSING: Comparison NACT followed by Sx Vs RCT

THE ISSUE OF ADJUVANT CHEMOTHERAPY!!! Disease progression after radical radio-chemotherapy: 35% Distant relapses are major in locally advanced cervical cancer after radical Rx Adjuvant CT was part of few trials of Chemo-radiation No proper large study evaluating Adj. CT

THE ISSUE OF ADJUVANT CHEMOTHERAPY!!! Women with Ca Cervix IIB IV A with KPS >70% with no evidence of PA LN Arm A (n= 259 pts) CCRT + Brachytherapy + Adj. CT Concurrent Chemo: Weekly Cis 40 mg/m2 + Gemcitabine 125mg/m2 Adjuvant chemo: 2 weeks after RT Cisplatin and Gemcitabine 2 cycles ARM B (n= 256 pts) CCRT+ BRT with Weekly Cis 40mg/m2 Α. Ι. ΔΗΜΟΠΟΥΛΟΣ Ο ΡΟΛΟΣ ΤΗΣ ΑΚΤΙΝΟΘΕΡΑΠΕΙΑΣ ΣΤΟΝ ΠΡΩΙΜΟ Duenas-Gonzalez ΚΑΡΚΙΝΟ ΤΟΥ ΤΡΑΧΗΛΟΥ et ΤΗΣ al, ΜΗΤΡΑΣ JCO 2011

THE ISSUE OF ADJUVANT CHEMOTHERAPY!!! Arm A - More Grade 3-4 toxicities (p<0.001) Haematologic Toxicity: Grade 3-4 ; 71.9% Vs 23.9 % Non haematologic toxicities: Vomiting & diarrhea more in arm A (p=0.002) Hospitalization during treatment: Arm A -30 pts & Arm B -11 pts (p=0.02) 3 deaths in arm A 2 due to sepsis and bowel perforation & 1 due to acute encephalopathy Late toxicities slightly higher in Arm A: Grade 4 GI : 2.3 % Vs 0% Duenas-Gonzalez et al, JCO 2011

THE ISSUE OF ADJUVANT CHEMOTHERAPY!!! 3 Y PFS 74.4% Vs 69% (p=0.029) Median PFS- HR 0.68 Statistically significant improvement in median PFS Conclusion: Gemcitabine + Cisplatin CRT followed by Brachy & adjuvant gem/cis CT improved survival outcomes with increased but clinically manageable toxicity compared to standard Rx Criticism: statistical design was changed (OS to PFS), toxicity issues not solved Duenas-Gonzalez et al, JCO 2011

THE ISSUE OF ADJUVANT CHEMOTHERAPY ONGOING STUDIES!!! OUTBACK TRIAL MULTICENTRIC PHASE III STUDY Cisplatin based concurrent chemoradiation Vs CCRT followed by Pacli + Carbo x 3 cycles OUTBACK TRIAL - ONGOING

OTHER ONGOING STUDIES!!! Induction Chemotherapy followed by Concomitant Chemo-Radiation in Advanced Stage Carcinoma Cervix: A Phase III Randomized Trial (INTERLACE Study - NCT01566240) Carcinoma Cervix Stage FIGO Ib2-IVA 385 patients Concomitant chemo radiotherapy weekly Cisplatin (40 mg/m2 x 4-5 #) 385 patients Induction chemotherapy with weekly x 6 Paclitaxel (80 mg/m2) + Carboplatin Concomitant chemoradiotherapy Cisplatin (40 mg/m2 x 4-5 #) Outcomes: Primary: Overall Survival Secondary: Progression free Survival Acute toxicities Late Toxicities Initiated in 2012 Accrual period: 4 years Completion: 2021 INTERLACE TRIAL - ONGOING

BIOLOGICAL AGENTS!!! Only Phase I-II studies available not able to draw any conclusions

CONCLUSIONS LOCALLY ADVANCED DISEASE!!! CRT with Cisplatin extensively tested for cervical cancer Concomitant Chemo-radiation with wkly cisplatin (40 mg/m2) : STD of Care -CRT with weekly cisplatin recommended for FIGO Stage IB2 - IIB -CRT for FIGO Stage III-IVA: to be established further (CRACx study) Alternatives to Cisplatin: No much progress including biological agents Neo-adjuvant CT approaches: Investigational Adjuvant CT after CRT & Induction CT: Phase III studies ongoing