Optimal treatment in locally advanced cervical cancer

Figures & data

Table 1. Adjuvant chemotherapy trials

	LORVIDHAYA ET AL. [80]	DUENAS-GONZALEZ ET AL. [81,82]	TANG ET AL. [84]	TANGJITGAMOL ET AL. [85]
Years of enrollment	1988–1994	2002–2004	1998–2007	2015–2017
Number of patients	926	515	880	259
Stage (FIGO)	IIB to IVA	IIB to IVA	IIB to IVA	IIB to IVA
Other criteria	Stage IIB: only central tumor > 3 cm and/or half of the parametrium involved	Patients with positive PAo LN (1> cm) from imaging must be negative in biopsy	Patients with positive PAo LN from imaging received extended-field RT	Patients with PAo enlargement from imaging are excluded
Histology	SCC-ADC	SCC-ADC-ADSC and poorly differentiated	ADC-ADSC	SCC-ADC-ADSC
CCRT phase	mitomycine C + oral 5-FU	CCRT arm = cisplatin ACT arm = cisplatin + gemcitabine	cisplatin	cisplatin
ACT phase	oral 5-FU (3 cycles)	cisplatin + gemcitabine (2 cycles)	cisplatin + paclitaxel (2 cycles) + 1 cycle before CCRT	carboplatin + paclitaxel (3 cycles)
Median follow-up	89 months	46.9 months	60 months	27.4 months
Survival outcomes	DFS at 5 years = better only in CCRT arm OS = NS	PFS and OS = in favor of ACT arm	DFS = in favor of ACT arm	3-year PFS = NS 3-year OS = NS
Local relapse	Significantly higher in non-CCRT arms	NS	in favor of ACT arm	NS
Distant relapse	NS	lower in ACT arm	in favor of ACT arm	lower in ACT arm
Toxicity	increased in CCRT arm	grade 3–4 more frequent in ACT arm	leukopenia and thrombocytopenia significantly higher in ACT arm	grade 3–4 neutropenia higher in ACT arm

ACT = adjuvant chemotherapy; ADSC = adenosquamous carcinoma; ADC = adenocarcinoma; CCRT = concomitant chemoradiotherapy; DFS = disease-free survival; FIGO = International Federation of Gynecology and Obstetrics; 5-FU = 5-fluoro-uracil; LN = lymph node; NACT = neo-adjuvant chemotherapy; NS = not significant; OS = overall survival; PAo = para-aortic; PFS = progression-free survival; RT = radiotherapy; SCC = squamous cell carcinoma

Table 2. Neo-adjuvant chemotherapy followed by surgery versus surgery

	RYDZEWSKA ET AL. [87]	KIM ET AL. [88]	ZHAO ET AL. [89]
Years of enrollment	1987–2005	1987–2010	1997–2016
Number of trials	6 RCTs	5 RCTs + 4 observational	13 studies
Number of patients	1078	1784	2158
Stage (FIGO)	IB to IIIB	IB1 to IIA	IB to IIB
Histology	SCC-ADC-ADSC	SCC-ADC-ADSC	SCC-ADC-ADSC
NACT phase	cisplatin-based CT + vincristine/bleomycin/5-FU or mitomycin C	cisplatin or carboplatin – based CT + vincristine/bleomycin/5-FU/mitomycin C or paclitaxel	various regimens
Surgery	type III Piver radical HT -pelvic lymphaD (3 trials) -pelvic + PAo lymphaD (2 trials)	type II or IV HT -pelvic lymphaD (all trials) -PAo lymphaD (if need)	radical HT -lymphaD = NE
Survival outcomes	PFS and OS = in favor of NACT arm	PFS = NS OS = NS OS (observational trials) = poorer in NACT arm	PFS and OS = NS -sub-analysis (IB2-IIB) PFS = NS OS = better in NACT arm
Local Relapse	NS	NS	NS -sub-analysis (IB2-IIB) = decreased in NACT arm
Distant relapse	NS	decreased in NACT arm	NS -sub-analysis (IB2-IIB) = decreased in NACT arm

ADC = adenocarcinoma; ADSC = adenosquamous carcinoma; CT = chemotherapy; FIGO = International Federation of Gynecology and Obstetrics; 5-FU = 5-fluoro-uracil; HT = hysterectomy; lymphaD = lymphadenectomy; NACT = neo-adjuvant chemotherapy; NE = not evaluated; NS = not significant; OS = overall survival; PAo = para-aortic; PFS = progression-free survival; RCTs = randomized controlled trials; SCC = squamous cell carcinoma

Table 3. Neo-adjuvant chemotherapy followed by surgery versus concomitant chemoradiation

	GUPTA ET AL. [91]	KENTER ET AL. [92]
Years of enrollment	2003–2015	2002–2014
Number of patients	635	626
Stage (FIGO 1994)	IB2-IIA or IIB	IB2-IIA2-IIB
Histology	SCC	SCC-ADC-ADSC
First endpoint	DFS	OS at 5 years
Median follow-up	58.5 months	96 months
NACT phase	carboplatin + paclitaxel (3 cycles)	-cisplatin monotherapy (dose at least 225 mg/m^2) (46%) -doublet (+ paclitaxel) (20%) -triplet (+ paclitaxel + ifosfamide) (19%) -other (15%)
CCRT phase	-EBRT 40 Gy (20 x 2 Gy) + ICBT (LDR 2 × 30 Gy or HDR 5 × 7 Gy) -CT = cisplatin weekly	-EBRT 45–50 Gy (pelvis) with external boost or BT -CT = cisplatin weekly
Adjuvant treatment after protocol completion	*in NACT arm, -21.5% crossover to CCRT (pre-surgery and intraoperative unresectable disease) -13.3% = adjuvant CCRT -9.8% = adjuvant RT alone	*in NACT arm, -24% = no surgery (34% CT toxicity; 24% progressive; 16% insufficient response; 14% patient refused) -14% = adjuvant RT *in CCRT arm, -6% = no CCRT (55% patient refused; 25% protocol violation, …) -4% = surgery
Survival outcomes	5 year PFS = in favor of CCRT 5 year OS = NS	OS (ITT and completed treatment) = NS PFS (ITT) = in favor of NACT arm PFS (completed treatment) = NS
Survival sub-analysis	*stages IB2 or IIA: DFS = NS	*stage IB2: OS = trend in favor of NACT arm *stage IIB: OS = trend in favor of CCRT arm
Toxicity	-grade 3–4 thrombocytopenia = higher in NACT arm -grade 3–4 bladder and GI = NS -AEs at 90 days, higher in CCRT arm (rectal, bladder and vaginal) -AEs at 24 months, higher in CCRT arm (only vaginal)	-treatment period grade 3–4: higher in NACT arm (GI and hematologic) -follow-up period grade 3–4: higher in CCRT arm (GI and GU)

ADC = adenocarcinoma; ADSC = adenosquamous carcinoma; AEs = adverse events; BT = brachytherapy; CCRT = concomitant chemoradiotherapy; CT = chemotherapy; DFS = disease-free survival; EBRT = external-beam radiotherapy; FIGO = International Federation of Gynecology and Obstetrics; GI = gastro-intestinal; GU = genito-urinary; HDR = high-dose rate; IC = intra-cavitary; ITT = intention-to-treat; LDR = low-dose rate; NACT = neo-adjuvant chemotherapy; NS = not significant; OS = overall survival; PFS = progression-free survival; RT = radiotherapy; SCC = squamous cell carcinoma

Figure 1. Optimal treatment for LACC: step by step. AUC = area under the curve; EBRT = external-beam radiotherapy; [¹⁸F]FDG-PET/CT = ¹⁸F-2ʹ-deoxy-2ʹ fluorodeoxyglucose; HDR = high-dose rate; IGABT = image-guided adaptive brachytherapy; IGRT = image-guided radiotherapy; IMRT = intensity-modulated radiation therapy; LN = lymph node; MRI = magnetic resonance imagery; OTT = overall treatment time; PAo = para-aortic; PDR = pulsed-dose rate; RT = radiotherapy; 3D = three-dimensional; VMAT = volumetric arc therapy

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