Adjuvant (post‐surgery) chemotherapy for early stage epithelial ovarian cancer

Theresa A Lawrie; Brett A Winter‐Roach; Pauline Heus; Henry C Kitchener

doi:10.1002/14651858.CD004706.pub5

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Figure 4

Risk of death in the 10 years after surgery for women with early stage ovarian cancer treated with adjuvant chemotherapy: In the control group 33 women had died compared to 25 (20 to 31) out of 100 in the active treatment group.

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Figure 5

Risk of cancer progression/recurrence in the 10 years after surgery for women with early stage ovarian cancer treated with adjuvant chemotherapy: in the control group 39 women had progressive disease compared to 28 (23 to 34) out of 100 in the active treatment group.

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Figure 6

Risk of death in the 10 years after surgery for women with high risk early stage ovarian cancer treated with adjuvant chemotherapy: in the control group 44 people out of 100 died, compared to 32 (95% CI 23 to 43) out of 100 for the active treatment group.

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Figure 7

Risk of cancer progression/recurrence in the 10 years after surgery for women with high risk early stage ovarian cancer treated with adjuvant chemotherapy: in the control group 50 women had progressive disease compared to 32 (23 to 45) out of 100 in the active treatment group.

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Figure 1

Study flow diagram of search results (up to August 2011).

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Figure 2

Study flow diagram of the literature search results (24 March 2015).

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Figure 3

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.

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Analysis 1.1

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 1 Overall survival (5 yr).

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Analysis 1.2

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 2 Deaths total (5 yr).

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Analysis 1.3

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 3 Overall survival (10 yr).

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Analysis 1.4

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 4 Death total (10 yr).

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Analysis 1.5

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 5 Progression‐free survival (5 yr).

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Analysis 1.6

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 6 Progression total (5 yr).

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Analysis 1.7

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 7 Progression‐free survival (10 yr).

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Analysis 1.8

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 8 Progression total (10 yr).

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Analysis 1.9

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 9 Disease‐specific survival (5 yr).

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Analysis 1.10

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 10 Disease‐specific survival (10 yr).

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Analysis 1.11

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 11 Subgroup analysis by staging: 5‐yr OS.

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Analysis 1.12

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 12 Subgroup analysis by staging: 10 yr DSS.

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Analysis 1.13

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 13 Subgroup analysis by staging: death from ovarian cancer (10 years).

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Analysis 1.14

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 14 Subgroup analysis by staging: 5‐yr PFS.

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Analysis 1.15

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 15 Subgroup analysis by staging: 10‐yr PFS.

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Analysis 1.16

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 16 Subgroup analysis by staging: progression of ovarian cancer (10 years).

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Analysis 1.17

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 17 Subgroup analysis by risk: 10‐yr OS.

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Analysis 1.18

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 18 Subgroup analysis by risk: 10‐yr PFS.

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Analysis 1.19

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 19 Subgroup analysis by risk: progression at 10 yrs.

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Analysis 1.20

Comparison 1 Adjuvant chemotherapy versus observation, Outcome 20 Subgroup analysis by risk: deaths by 10 yrs.

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Summary of findings for the main comparison. Summary of main findings

Adjuvant chemotherapy compared with observation for early stage ovarian cancer (primary review outcomes)
Patient or population: women with stage I/II epithelial ovarian cancer Settings: hospital and outpatient Intervention: chemotherapy following surgery Comparison: observation following surgery
Outcomes	Illustrative comparative risks		HR (95% CI) Chemotherapy versus observation	Number of participants ( studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk (Observation)	Corresponding risk (Chemotherapy)	HR (95% CI) Chemotherapy versus observation	Number of participants ( studies)	Quality of the evidence (GRADE)	Comments
Overall 5‐year survival¹	22 deaths out of 100 women	16 out of 100 women (12 to 20)	HR 0.71 (0.53 to 0.93)	1008 women (three studies)	⊕⊕⊕⊕ high	I² statistic = 0% P = 0.01 HR < 1 indicates a clinical advantage for adjuvant chemotherapy
Progression‐free 5‐year survival²	32 women with progressive disease out of 100 women	22 women with progressive disease out of 100 women (18 to 27)	HR 0.67 (0.53 to 0.84)	1170 women (four studies)	⊕⊕⊕⊕ high	I² statistic = 0% P = 0.0005 HR < 1 indicates a clinical advantage for adjuvant chemotherapy
Overall 10‐year³ survival	33 deaths out of 100 women	25 deaths out of 100 women (20 to 31)	HR 0.72 (0.57 to 0.92)	925 women (two studies)	⊕⊕⊕⊕ high	I² statistic = 0% P = 0.007 HR < 1 indicates a clinical advantage for adjuvant chemotherapy
Progression‐free 10‐year survival⁴	39 women with progressive disease out of 100 women	28 women with progressive disease out of 100 women (23 to 34)	HR 0.67 (0.53 to 0.83)	925 women (two studies)	⊕⊕⊕⊕ high	I² statistic = 0% P = 0.0004 HR < 1 indicates a clinical advantage for adjuvant chemotherapy
Adverse events	Not estimable. Trials did not report comparative rates of adverse events.
Abbreviations; CI: confidence interval; HR: hazard ratio; RR: risk ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹The illustrative assumed and corresponding 5‐year risks were based on the RR (dichotomous data) from Analysis 1.2 (RR 0.72, 95% CI 0.56 to 0.93; 1089 participants; 4 studies; I² statistic = 0%), where the assumed risk was the mean observation group risk. ²The illustrative assumed and corresponding 5‐year risks were based on the RR (dichotomous data) from Analysis 1.6 (RR 0.69, 95% CI 0.57 to 0.84; 1089 participants; 4 studies; I² statistic = 0%), where the assumed risk was the mean observation group risk. ³The illustrative assumed and corresponding 10‐year risks were based on the RR (dichotomous data) from Analysis 1.4 (RR 0.76, 95% CI 0.62 to 0.94; 923 participants; 2 studies), where the assumed risk was the mean observation group risk. ⁴The illustrative assumed and corresponding 10‐year risks were based on the RR (dichotomous data) from Analysis 1.8 (RR 0.72, 95% CI 0.60 to 0.87; 925 participants; 2 studies), where the assumed risk was the mean observation group risk.

Summary of findings for the main comparison. Summary of main findings

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Table 1. Staging of ovarian cancer

Stage	Description
Ia	Disease confined to one ovary with no capsular involvement. Peritoneal washings/cytology negative.
Ib	Disease confined to both ovaries with no capsular involvement. Peritoneal washings/cytology negative.
Ic	Disease confined to the ovary/ovaries but ovarian capsulae involved or cyst rupture
IIa	Extension to uterus or fallopian tubes
IIb	Extension to other pelvic tissues
IIc	As for IIa or IIb but one or both ovaries have ruptured capsule or surface tumour; malignant ascites or positive peritoneal washings
IIIa	Histologically confirmed microscopic seeding of abdominal peritoneal surfaces and negative retroperitoneal lymph nodes
IIIb	Histologically confirmed implants of abdominal peritoneal surfaces less than 2 cm and negative retroperitoneal lymph nodes
IIIc	Histologically confirmed implants of abdominal peritoneal surfaces greater than 2 cm or positive retroperitoneal lymph nodes
IV	Distant metastases (including liver parenchyma/positive pleural fluid cytology)

Table 1. Staging of ovarian cancer

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Table 2. RCTs of adjuvant treatment: description and quality assessment

Study ID	Recruitment period	Staging	Comparison	Randomisation	Intention to treat	5‐year follow‐up
Smith 1975	1969 to 1974	No	CT versus RT	Unspecified	No	Incomplete
Dembo 1979	1971 to 1975	No	RT versus RT+CT	Stratified	No	Median 52 months
Hreshchyshyn 1980	1971 to 1978	No	CT versus RT versus NA	Unspecified	No	No
Sigurdsson 1982	1975 to 1978	No	NT versus CT, RT versus CT or (RT + CT)	Stratified, quasi‐randomised	No	Yes
Sevelda 1987	1980 to 1985	Yes complete in 60.5%	NA versus RT versus (RT + CT)	Unspecified	No	Median 42 months
Grönroos 1984	1976 to 1978	No	NA versus RT and NA versus CT	Randomised by birth month (quasi‐randomisation)	No	3‐year follow‐up
Klaassen 1988	1975 to 1984	No	CT versus RT versus IPR	Central telephone	Yes	Median 8 years
Sell 1990	1981 to 1987	Complete	RT versus (RT + CT)	Block randomisation	Yes	4 years
Young 1990	1976	Complete	CT versus NA or IPR	Central, computer stratified	Yes	> 6 years
Young 2000 Bell 2006		Complete	3 x CT versus 6 x CT	Central, computerised	Yes	> 6 years
Young 2003		Complete	CT versus IPR	Central, computerised	Yes
Vergote 1992	1982 to 1988	Complete	CT versus IPR	Central, computer stratified	Yes	Median 62 months
Chiara 1994	1985 to 1989	Complete in 87%	CT versus RT	Central, computerised	Yes
Bolis 1995	1983 to 1990	Complete	CT versus NA or IPR	Central, random generated numbers	Yes	Yes
Tropé 2000	1992 to 1997	Complete	CT versus NA	Central, computerised	Yes	Median 46 months
Kojs 2001	1990 to 1996	Complete	CT versus RT	Method not explicit	Yes	Yes
ICON1 2003	1990 to 2001	Incomplete	CT versus NA	Central computerised	Yes	Median 51 months
ACTION 2003	1990 to 2000	Complete	CT versus NA	Central, computerised	Yes	Median 66 months
Mannel 2011 (GOG 175)		Complete	CT + maintenance versus CT alone	Central, computerised	Yes	Yes
Abbreviations: CT: chemotherapy; RT: radiotherapy; IPR: intra‐peritoneal radio‐isotope therapy; NA: no additional treatment.

Table 2. RCTs of adjuvant treatment: description and quality assessment

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Table 3. Trials of adjuvant chemotherapy versus no further treatment

Study ID	Participants	Intervention	5‐year survival rates	5‐year survival/statistics	10‐year survival rates	Adverse effects	Comments
ICON1 2003	447 FIGO I‐III 93% FIGO stage 1	Immediate adjuvant platinum‐based chemotherapy versus treatment on progression	OS 79% (adjuvant arm) versus70% ( no treatment)	HRs OS: HR 0.66; 95% CI 0.45 to 0.97; P = 0.03	OS 73% (adjuvant arm) versus 64% (no treatment)	Not reported	Survival improvement with adjuvant therapy
ACTION 2003	448 FIGO Ia‐Ib grade II‐III FIGO Ic‐IIa FIGO I‐IIa clear cell	Immediate adjuvant platinum‐based chemotherapy versus treatment on progression Cisplatin dose = 75 mg/m² Carboplatin dose = 350 mg/m²	OS 85% (adjuvant arm) versus 78% (no treatment)	HRs OS: HR 0.69; 95% CI 0.44 to 1.08; P = 0.10 RFS: HR 0.63; 95% CI 0.43 to 0.92; P = 0.02	OS 77% (adjuvant arm) versus 70% (no treatment)	Not reported	Subgroup analysis showed that non‐optimally staged patients in observation arm had significantly worse survival
Tropé 2000	162 high risk stage I 36% patients had low‐volume residual disease	Carboplatin 6 cycles Q28/7 AUC = 7 versus chemo at progression	No difference between arms DFS 70% versus 71%, OS 86% versus 85%	Log rank test DFS P = 0.41 OS P = 0.43	NR	HRs DFS: HR 0.98; 95% CI 0.52 to 1.83 DSS: HR 0.94; 95% CI 0.37 to 2.36	Not reported
Young 1990	48 treatment 44 observation	Melphalan versus no further treat	DFS 91% versus 98% OS 94% versus 98%	Log rank test DFS P = 0.41 OS P = 0.43	NR	Melphalan: 16% had severe myelosuppression. 26% had gastrointestinal side effects.One death: myeloproliferative disorder aplastic anaemia 6 years after completing treatment.	Trial under powered to show any real differences
Bolis 1995	85 FIGO (1976) I A‐I B Grade 2 and 3	Cisplatin 50 mg/m² × 6 cycles Q28/7 versus no further treatment	DFS 83% versus 64% OS 88% versus 82%	HRs DFS: HR 0.50; 95% CI 0.21 to 1.19; P = 0.17 OS: HR 1.20; 95% CI 0.46 to 3.1; P = 0.71	NR	Nausea and vomiting in more than two‐thirds of patients in cisplatin arm. Severe in less than 10%. Leucopenia 14%; thrombocytopenia 8%; neurological toxicity 6%; renal toxicity 7%	There were patients with residual disease in both arms
Abbreviations; CI: confidence interval; DFS: disease‐free survival; HR: hazard ratio; OS: overall survival; RFS: recurrence‐free survival; AUC: area under the concentration curve; NR: not reported.

Table 3. Trials of adjuvant chemotherapy versus no further treatment

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Table 4. 10‐year survival rates of adjuvant chemotherapy versus observation according to risk

10 year survival outcomes for women with early stage ovarian cancer	Adjuvant chemotherapy		Observation		P value
	n/N	%	n/N	%	P value
Risk of death (all early stage disease)¹	118/465	25%	152/460	33%	0.009
Risk of progression or death (all early stage disease)¹	132/465	28%	181/460	39%	0.0005
Risk of death (low/intermediate risk disease)²	19/101	19%	21/97	22%	NS
Risk of progression or death (low/intermediate risk disease)²	22/101	22%	24/97	25%	NS
Risk of death (high risk disease)²	31/106	29%	48/110	44%	0.03
Risk of progression or death (high risk disease)²	34/106	32%	55/110	50%	0.009
¹Based on ACTION 2003 and ICON1 2003 10‐year follow‐up data. ²Based on ICON1 2003 10‐year follow‐up subgroup data. Abbreviations: NS: not statistically significant;

Table 4. 10‐year survival rates of adjuvant chemotherapy versus observation according to risk

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Comparison 1. Adjuvant chemotherapy versus observation

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival (5 yr) Show forest plot	3	1008	Hazard Ratio (Random, 95% CI)	0.71 [0.53, 0.93]

2 Deaths total (5 yr) Show forest plot	4	1089	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.56, 0.93]

3 Overall survival (10 yr) Show forest plot	2	925	Hazard Ratio (Random, 95% CI)	0.72 [0.57, 0.92]

4 Death total (10 yr) Show forest plot	2	923	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.62, 0.94]

5 Progression‐free survival (5 yr) Show forest plot	4	1170	Hazard Ratio (Random, 95% CI)	0.67 [0.53, 0.84]

6 Progression total (5 yr) Show forest plot	4	1089	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.57, 0.84]

7 Progression‐free survival (10 yr) Show forest plot	2	925	Hazard Ratio (Random, 95% CI)	0.67 [0.53, 0.83]

8 Progression total (10 yr) Show forest plot	2	925	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.60, 0.87]

9 Disease‐specific survival (5 yr) Show forest plot	1		Hazard Ratio (Random, 95% CI)	Subtotals only

10 Disease‐specific survival (10 yr) Show forest plot	1		Hazard Ratio (Random, 95% CI)	Subtotals only

11 Subgroup analysis by staging: 5‐yr OS Show forest plot	3		Hazard Ratio (Random, 95% CI)	Subtotals only

11.1 Optimal staging	2	234	Hazard Ratio (Random, 95% CI)	1.22 [0.63, 2.37]
11.2 Suboptimal staging	2	772	Hazard Ratio (Random, 95% CI)	0.63 [0.46, 0.85]
12 Subgroup analysis by staging: 10 yr DSS Show forest plot	1		Hazard Ratio (Random, 95% CI)	Subtotals only

12.1 Optimal staging	1	151	Hazard Ratio (Random, 95% CI)	1.58 [0.61, 4.09]
12.2 Suboptimal staging	1	295	Hazard Ratio (Random, 95% CI)	0.58 [0.35, 0.96]
13 Subgroup analysis by staging: death from ovarian cancer (10 years) Show forest plot	2	923	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.54, 1.12]

13.1 Optimal staging	1	151	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.64, 3.79]
13.2 Suboptimal staging	2	772	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.54, 0.92]
14 Subgroup analysis by staging: 5‐yr PFS Show forest plot	4	1168	Hazard Ratio (Random, 95% CI)	0.64 [0.52, 0.78]

14.1 Optimal staging	2	234	Hazard Ratio (Random, 95% CI)	0.67 [0.36, 1.22]
14.2 Suboptimal staging	3	934	Hazard Ratio (Random, 95% CI)	0.64 [0.50, 0.82]
15 Subgroup analysis by staging: 10‐yr PFS Show forest plot	2	923	Hazard Ratio (Random, 95% CI)	0.66 [0.53, 0.83]

15.1 Optimal staging	1	151	Hazard Ratio (Random, 95% CI)	0.73 [0.38, 1.42]
15.2 Suboptimal staging	2	772	Hazard Ratio (Random, 95% CI)	0.65 [0.52, 0.83]
16 Subgroup analysis by staging: progression of ovarian cancer (10 years) Show forest plot	2	923	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.58, 0.87]

16.1 Optimal staging	1	151	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.39, 1.26]
16.2 Suboptimal staging	2	772	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.58, 0.88]
17 Subgroup analysis by risk: 10‐yr OS Show forest plot	1	414	Hazard Ratio (Random, 95% CI)	0.66 [0.38, 1.13]

17.1 Low/intermediate risk	1	198	Hazard Ratio (Random, 95% CI)	0.91 [0.49, 1.69]
17.2 High risk	1	216	Hazard Ratio (Random, 95% CI)	0.52 [0.33, 0.81]
18 Subgroup analysis by risk: 10‐yr PFS Show forest plot	1	414	Hazard Ratio (Random, 95% CI)	0.64 [0.34, 1.21]

18.1 Low/medium	1	198	Hazard Ratio (Random, 95% CI)	0.92 [0.52, 1.64]
18.2 High	1	216	Hazard Ratio (Random, 95% CI)	0.48 [0.32, 0.73]
19 Subgroup analysis by risk: progression at 10 yrs Show forest plot	1	414	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.53, 0.95]

19.1 Low/intermediate risk	1	198	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.53, 1.46]
19.2 High risk	1	216	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.46, 0.90]
20 Subgroup analysis by risk: deaths by 10 yrs Show forest plot	1	414	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.53, 0.98]

20.1 Low/intermediate risk	1	198	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.50, 1.51]
20.2 High risk	1	216	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.47, 0.96]

Comparison 1. Adjuvant chemotherapy versus observation

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