Chemotherapy and radiotherapy for advanced pancreatic cancer

Venessa Chin; Adnan Nagrial; Katrin Sjoquist; Chelsie A O'Connor; Lorraine Chantrill; Andrew V Biankin; Rob JPM Scholten; Desmond Yip

doi:10.1002/14651858.CD011044.pub2

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Figure 1

1 Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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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 Anti‐cancer therapy versus best supportive care, Outcome 1 Overall survival.

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Analysis 2.1

Comparison 2 Various types of chemotherapy versus gemcitabine, Outcome 1 Overall survival.

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Analysis 2.2

Comparison 2 Various types of chemotherapy versus gemcitabine, Outcome 2 Progression‐free survival.

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Analysis 2.3

Comparison 2 Various types of chemotherapy versus gemcitabine, Outcome 3 Degradation of QoL at 6 months.

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Analysis 2.4

Comparison 2 Various types of chemotherapy versus gemcitabine, Outcome 4 Response rates.

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Analysis 2.5

Comparison 2 Various types of chemotherapy versus gemcitabine, Outcome 5 Grade 3/4 anaemia.

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Analysis 2.6

Comparison 2 Various types of chemotherapy versus gemcitabine, Outcome 6 Grade 3/4 neutropenia.

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Analysis 2.7

Comparison 2 Various types of chemotherapy versus gemcitabine, Outcome 7 Grade 3/4 thrombocytopenia.

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Analysis 2.8

Comparison 2 Various types of chemotherapy versus gemcitabine, Outcome 8 Grade 3/4 nausea.

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Analysis 2.9

Comparison 2 Various types of chemotherapy versus gemcitabine, Outcome 9 Grade 3/4 diarrhoea.

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Analysis 3.1

Comparison 3 Gemcitabine combinations versus gemcitabine alone, Outcome 1 Overall survival.

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Analysis 3.2

Comparison 3 Gemcitabine combinations versus gemcitabine alone, Outcome 2 Progression‐free survival.

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Analysis 3.3

Comparison 3 Gemcitabine combinations versus gemcitabine alone, Outcome 3 Response rates.

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Analysis 3.4

Comparison 3 Gemcitabine combinations versus gemcitabine alone, Outcome 4 Grade 3/4 anaemia.

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Analysis 3.5

Comparison 3 Gemcitabine combinations versus gemcitabine alone, Outcome 5 Grade 3/4 neutropenia.

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Analysis 3.6

Comparison 3 Gemcitabine combinations versus gemcitabine alone, Outcome 6 Grade 3/4 thrombocytopenia.

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Analysis 3.7

Comparison 3 Gemcitabine combinations versus gemcitabine alone, Outcome 7 Grade 3/4 nausea.

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Analysis 3.8

Comparison 3 Gemcitabine combinations versus gemcitabine alone, Outcome 8 Grade 3/4 diarrhoea.

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Analysis 3.9

Comparison 3 Gemcitabine combinations versus gemcitabine alone, Outcome 9 Grade 3/4 neuropathy.

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Analysis 3.10

Comparison 3 Gemcitabine combinations versus gemcitabine alone, Outcome 10 Grade 3/4 fatigue.

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Analysis 4.1

Comparison 4 Fluoropyrimidine combinations versus fluoropyrimidine alone, Outcome 1 Overall survival.

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Analysis 4.2

Comparison 4 Fluoropyrimidine combinations versus fluoropyrimidine alone, Outcome 2 Progression‐free survival.

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Analysis 4.3

Comparison 4 Fluoropyrimidine combinations versus fluoropyrimidine alone, Outcome 3 Response rates.

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Analysis 4.4

Comparison 4 Fluoropyrimidine combinations versus fluoropyrimidine alone, Outcome 4 Grade 3/4 anaemia.

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Analysis 4.5

Comparison 4 Fluoropyrimidine combinations versus fluoropyrimidine alone, Outcome 5 Grade 3/4 neutropenia.

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Analysis 4.6

Comparison 4 Fluoropyrimidine combinations versus fluoropyrimidine alone, Outcome 6 Grade 3/4 thrombocytopenia.

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Analysis 4.7

Comparison 4 Fluoropyrimidine combinations versus fluoropyrimidine alone, Outcome 7 Grade 3/4 fatigue.

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Analysis 4.8

Comparison 4 Fluoropyrimidine combinations versus fluoropyrimidine alone, Outcome 8 Grade 3/4 nausea.

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Analysis 4.9

Comparison 4 Fluoropyrimidine combinations versus fluoropyrimidine alone, Outcome 9 Grade 3/4 diarrhoea.

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Summary of findings for the main comparison. Anti‐cancer therapy versus best supportive care for advanced pancreatic cancer

Anti‐cancer therapy versus best supportive care for advanced pancreatic cancer
Person or population: advanced pancreatic cancer Setting: first‐line therapy Intervention: anti‐cancer therapy Comparison: best supportive care
Outcomes	*Anticipated risk of death (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments	Toxicity and QoL
	Risk with best supportive care	Risk with anti‐cancer therapy
Overall survival	Study population		HR 1.08 (0.88 to 1.33)	298 (4 RCTs)	⊕⊕⊕⊝ Moderate^a	—	The analysis showed that toxicity data were inconsistently reported. Most studies reporting this outcome noted that gastrointestinal adverse events were the most frequent, occurring in between 15% to 31%. 1 study noted haematological toxicity was present in 81.5% of people. 2 out of the 3 studies that analysed QoL demonstrated a benefit with anti‐cancer therapy. 1 study showed no difference between the 2 groups.
	707 per 1000	734 per 1000 (660 to 804)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HR: hazard ratio; RCT: randomised controlled trial.
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aConfidence interval include both benefit and harm; optimal information size not met.

Summary of findings for the main comparison. Anti‐cancer therapy versus best supportive care for advanced pancreatic cancer

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Summary of findings 2. Various types of chemotherapy versus gemcitabine for advanced pancreatic cancer

Various types of chemotherapy versus gemcitabine for advanced pancreatic cancer
Person or population: advanced pancreatic cancer Setting: first‐line therapy Intervention: various types of chemotherapy Comparison: gemcitabine
Outcomes	*Anticipated risk of death (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments	Toxicity and QoL
	Risk with gemcitabine	Risk with various types of chemotherapy
Overall survival ‐ 5FU	Study population		HR 1.69 (1.26 to 2.27)	126 (1 RCT)	⊕⊕⊕⊝ Moderate^a	Only 1 study	More toxicity was seen in the gemcitabine arm. Clinical benefit was improved in the gemcitabine arm
	825 per 1000	948 per 1000 (889 to 981)
Overall survival ‐ FOLFIRINOX	Study population		HR 0.51 (0.43 to 0.60)	652 (2 RCTs)	⊕⊕⊕⊝ Moderate^b	—	More toxicity was seen in the FOLFIRINOX arm. Longer time to degradation of QoL in FOLFIRINOX arm
	794 per 1000	554 per 1000 (494 to 613)
Overall survival ‐ Fixed dose rate gemcitabine	Study population		HR 0.79 (0.66 to 0.94)	644 (2 RCTs)	⊕⊕⊕⊕ High	—	More toxicity in the fixed‐dose rate arm. QoL was not tested
	880 per 1000	812 per 1000 (753 to 863)
Overall survival ‐ CO‐101	Study population		HR 1.07 (0.86 to 1.34)	367 (1 RCT)	⊕⊕⊕⊝ Moderate^c	Only 1 study	Toxicity was similar in both arms, QoL was not tested
	854 per 1000	872 per 1000 (809 to 924)
Overall survival ‐ ZD9331	Study population		HR 0.86 (0.42 to 1.76)	55 (1 RCT)	⊕⊕⊕⊝ Moderate^a,c	Only 1 study	Toxicity was similar in both arms, QoL was not tested
	560 per 1000	506 per 1000 (292 to 764)
Overall survival ‐ Exatecan	Study population		HR 1.27 (0.96 to 1.68)	339 (1 RCT)	⊕⊕⊕⊝ Moderate^c	Only 1 study	Toxicity was similar in both arms, QoL was superior in the gemcitabine arm
	776 per 1000	851 per 1000 (763 to 919)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HR: hazard ratio; RCT: randomised controlled trial.
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aSmall sample size; optimal information size not met. ^bModerate statistical heterogeneity. ^cConfidence interval includes both benefit and harm.

Summary of findings 2. Various types of chemotherapy versus gemcitabine for advanced pancreatic cancer

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Summary of findings 3. Gemcitabine combinations versus gemcitabine alone for advanced pancreatic cancer

Gemcitabine combinations versus gemcitabine alone for advanced pancreatic cancer
Person or population: advanced pancreatic cancer Setting: first‐line therapy Intervention: gemcitabine combinations Comparison: gemcitabine alone
Outcomes	*Anticipated risk of death (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments	Toxicity and QoL
	Risk with gemcitabine alone	Risk with gemcitabine combinations
Overall survival ‐ Gemcitabine plus platinum agent	Study population		HR 0.94 (0.81 to 1.08)	1140 (6 RCTs)	⊕⊕⊝⊝ Low^a,b	—	More toxicity in the combination arm with no differences shown in QoL
	705 per 1000	683 per 1000 (628 to 733)
Overall survival ‐ Gemcitabine plus fluoropyrimidine	Study population		HR 0.89 (0.81 to 0.97)	2718 (10 RCTs)	⊕⊕⊕⊕ High	—	More toxicity in the combination arm. 2 studies showed no difference in QoL, 2 studies showed an improved QoL in the combination arm
	690 per 1000	648 per 1000 (613 to 679)
Overall survival ‐ Gemcitabine plus topoisomerase inhibitor	Study population		HR 1.01 (0.87 to 1.16)	839 (3 RCTs)	⊕⊕⊕⊕ High	—	More toxicity in the combination arm. In 1 study, QoL was not different between the 2 arms
	800 per 1000	803 per 1000 (753 to 845)
Overall survival ‐ Gemcitabine plus taxane	Study population		HR 0.72 (0.62 to 0.84)	861 (1 RCT)	⊕⊕⊕⊕ High	1 study only	More toxicity in the combination arm. QoL not measured
	779 per 1000	663 per 1000 (608 to 719)
Overall survival ‐ Gemcitabine plus other combinations of chemotherapy	Study population		HR 0.55 (0.39 to 0.79)	166 (2 RCTs)	⊕⊕⊝⊝ Low^c,d,e	—	Toxicity measured in 1 study and was not different. QoL was shown to be improved in the combination arms in both studies
	850 per 1000	648 per 1000 (523 to 777)
Overall survival ‐ Gemcitabine plus other agent(s)	Study population		HR 0.79 (0.56 to 1.10)	767 (4 RCTs)	⊕⊕⊝⊝ Low^b,f		There was an increase in anaemia in the combination arm. 2 studies measured QoL and it was similar in both treatment arms
	825 per 1000	748 per 1000 (624 to 853)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HR: hazard ratio; RCT: randomised controlled trial.
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aTwo studies were in abstract form and could not have full assessment completed. ^bConfidence interval includes both benefit and harm. ^cOne study did not publish sufficient details to make a full assessment. ^dThere was moderate statistical heterogeneity. ^eOptimal information size not met. ^fHigh statistical heterogeneity which is likely due to the difference in agents used in the treatment arms.

Summary of findings 3. Gemcitabine combinations versus gemcitabine alone for advanced pancreatic cancer

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Summary of findings 4. Fluoropyrimidine combinations versus fluoropyrimidine alone for advanced pancreatic cancer

Fluoropyrimidine combinations versus fluoropyrimidine alone for advanced pancreatic cancer
Person or population: advanced pancreatic cancer Setting: first line therapy Intervention: fluoropyrimidine combinations Comparison: fluoropyrimidine alone
Outcomes	*Anticipated risk of death (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Toxicity and QoL
	Risk with fluoropyrimidine alone	Risk with fluoropyrimidine combinations
Overall survival	Study population		HR 0.84 (0.61 to 1.15)	491 (4 RCTs)	⊕⊕⊝⊝ Low^a,b	Toxicity was not different between the 2 treatment arms. QoL was measured in 1 study and showed an improvement in the combination arm
	838 per 1000	783 per 1000 (671 to 877)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HR: hazard ratio; RCT: randomised controlled trial.
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aHigh statistical heterogeneity. ^bConfidence interval includes both benefit and harm.

Summary of findings 4. Fluoropyrimidine combinations versus fluoropyrimidine alone for advanced pancreatic cancer

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Table 1. Median survival times and quality of life results of anti‐cancer therapy versus best supportive care

Study	Anti‐cancer therapy details	Median survival:anti‐cancer therapy vs best supportive care (months)	Quality of life
Andren‐Sandberg 1983	5FU + CCNU	5 vs 4	No difference in Karnofsky performance status (KPS) score
Frey 1981	5FU + CCNU	3.0 vs 3.9	Not addressed
Glimelius 1996	5FU + LV	6.0 vs 2.5	EORTC QLQ‐C30 results favoured the anti‐cancer therapy (NB: high rate of dropouts in the later time points)
Huguier 2001	5FU + LV + cisplatin	8.6 vs 7.0	Not addressed
Takada 1998	5FU + doxorubicin + MMC	4.9 vs 5.0	Not addressed
Xinopoulos 2008	Gemcitabine	5.25 vs 5.5	Superior QoL (EORTC QLQ‐C30) in the gemcitabine group during the 1st month (P = 0.028), no difference from the 2nd to the 4th month; in the 5th and 6th month superior QoL in the BSC group (P = 0.010 and < 0.001)
5FU: 5‐Fluorouracil; CCNU: chloroethylcyclohexylnitrosurea; EORTC QLQ‐C30: European Organisation for Research and Treatment of Cancer quality of life questionnaire for cancer patients; LV: leucovorin; MMC: 5FU+doxorubicin + mitomycin C

Table 1. Median survival times and quality of life results of anti‐cancer therapy versus best supportive care

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Table 2. Median survival times and quality of life results of various types of chemotherapy versus gemcitabine

Study	Type of other chemotherapy	Median survival:other chemotherapy vs gemcitabine (months)	Quality of life
Burris 1997	5FU	4.4 vs 5.7	Improved clinical benefit 4.8% vs 23.8%. Median time to benefit 7 vs 3 weeks. Duration of benefit 18 vs 13 weeks
Conroy 2011	FOLFIRINOX	11.1 vs 6.8	QLQ‐C30: decrease in Global Health Status and QoL scale at 3 months 17% vs 31%; at 6 months 31% vs 66% Median time to definitive deterioration: not reached vs 5.7 months
Singhal 2014	FOLFIRINOX	10.8 vs 7.4	Definitive degradation of QoL at six months: 29% vs 59%
Poplin 2013	CO‐101	5.2 vs 6.0	Not addressed
Smith 2003	ZD‐9331	5.0 vs 3.6	Not addressed
Poplin 2009	Fixed dose rate gemcitabine 1500 mg/m² over 150 min	6.2 vs 4.9	Not addressed
Tempero 2003	Fixed dose rate gemcitabine 1500 mg/m² at 10 mg/m²/min	8.0 vs 5.0	Not addressed
Cheverton 2004	Exatecan (DX‐8951f)	5.0 vs 6.6	Time to worsening of clinical benefit was longer in the gemcitabine group. Pain (3.7 vs 7.9 months; P = 0.0493), KPS (3.4 vs 4.6 months; P = 0.0111) and weight (2.3 vs 3.8 months; P = 0.0203). QoL measured with QLQ‐C3 and QLQ‐PAN26 were similar in the 2 groups
5FU: 5‐Fluorouracil; FOLFIRINOX: 5‐fluorouracil + irinotecan + oxaliplatin; QoL: quality of life; QLQ‐C30 and QLQ‐PAN26: general and pancreatic cancer specific QoL questionnaire.

Table 2. Median survival times and quality of life results of various types of chemotherapy versus gemcitabine

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Table 3. Median survival times and quality of life results of gemcitabine combinations versus gemcitabine alone

Study	Gemcitabine combination details	Median survival:gemcitabine combination vs gemcitabine alone (months)	Quality of life
Platinum combinations
Colucci 2002	Gemcitabine + cisplatin	7.5 vs 5.0	Not addressed
Colucci 2010	Gemcitabine + cisplatin	7.2 vs 8.3	The mean difference from baseline in global QoL (EORTC C30) was not significantly different between the 2 groups: 0.09 (gemcitabine/cisplatin) vs 6.20 (gemcitabine), P = 0.07
Heinemann 2006	Gemcitabine + cisplatin	7.5 vs 6.0	No difference was detected in the 2 groups with either the Spitzer index or the pain intensity score
Li 2004	Gemcitabine + cisplatin	5.6 vs 4.6	Clinical benefit (pain control, performance status, body weight gain) 29% vs 36% (P > 0.05); Quality adjusted life months 3.8 vs 5.6 (P < 0.001)
Louvet 2005	Gemcitabine + oxaliplatin	9.0 vs 7.1	Not addressed
Viret 2004	Gemcitabine + cisplatin	8.0 vs 6.7	Q‐TWiST results did not differ significantly between the 2 arms (EORTC C30)
Wang 2002	Gemcitabine + cisplatin	7.2 vs 9.1	Not addressed
Fluoropyrimidine combinations
Berlin 2002	Gemcitabine + 5FU (weekly)	6.7 vs 5.4	Not addressed
Cunningham 2009	Gemcitabine + capecitabine	7.1 vs 6.2	89% of people completed QoL questionnaires (EORTC QLQ‐C30 + ESPAC). No differences seen at baseline between the 2 groups and no differences across treatment groups at 3 or 6 months
Di Costanzo 2005	Gemcitabine + daily 5FU	7.5 vs 7.75	No differences were seen between the 2 groups in mean disturbed days after cycle 1 or 2 or mean of days a person would like to cancel treatment in cycle 1 or 2
Herrmann 2007	Gemcitabine + capecitabine	8.4 vs 7.2	CBR seen in 29% of people in combination arm and 20% of people in gemcitabine arm. Median duration of response 9.5 and 6.5 weeks, respectively (P < 0.02). No differences in QoL as measured by LASA
Lee 2017	Gemcitabine + capecitabine	10.3 vs 7.5	Not addressed
Ohkawa 2004	Gemcitabine + UFT	Not stated	Not addressed
Ozaka 2012	Gemcitabine + S1	13.7 vs 8.0	Not addressed
Riess 2005	Gemcitabine + 5FU (24 hour infusion) + FA	Not stated	Not addressed
Scheithauer 2003	Gemcitabine + capecitabine	9.5 vs 8.2	The gemcitabine + capecitabine arm had an improvement in pain (35.5 vs 20%), KPS (41.9 vs 27%), but not weight (9.7 vs 17%)
Ueno 2013	Gemcitabine + S1	10.1 vs 8.8	The gemcitabine + S1 group showed an improvement in QALYs 0.525 vs 0.401, P < 0.001
Topoisomerase combinations
Abou‐Alfa 2006	Gemcitabine + exatecan	6.2 vs 6.7	Not addressed
Rocha Lima 2004	Gemcitabine + irinotecan	6.3 vs 6.5	FACT‐Hep questionnaires were completed by 80% of people in irinotecan/gemcitabine group and 73% of the gemcitabine group during the first 30 weeks of the study. There were no differences between the 2 groups.
Stathopoulos 2006	Gemcitabine + irinotecan	6.4 vs 6.5	Not addressed
Taxane combinations
Von Hoff 2013	Gemcitabine + nab‐paclitaxel	8.5 vs 6.7	Not addressed
Other combination chemotherapy including gemcitabine
Petrioli 2015	Gemcitabine + oxaliplatin + capecitabine (GEMOXEL)	11.9 vs 7.1	The global QoL score was higher in the combination chemotherapy group at 2 months (61 vs 56) and 4 months (72 vs 66)
Reni 2005	Cisplatin/epirubicin/gemcitabine/5FU (PEFG)	Not stated	The EORTC‐QLQ Pan 26 questionnaire was done but the sample size was insufficient to obtain adequate statistical power to reliably detect differences between groups for multiple comparisons. People in PEFG group 20% to 44% more likely to have improvement in emotional functioning, overall quality of life, cognitive measures, pain, fatigue, indigestion, dyspnoea, appetite loss and flatulence. However, people in gemcitabine group had better scores for sexual function and body image
Other agents in combination with gemcitabine
Gansauge 2002	Gemcitabine + Ukrain	10.4 vs 5.2	Not addressed
Meng 2012	Gemcitabine + huachansu	5.2 vs 5.3	No significant differences were seen between the treatment groups with either the FACT‐G or MDASI assessments
Oettle 2005	Gemcitabine + pemetrexed	6.2 vs 6.3	People in the gemcitabine group had better financial difficulties score, better physical functioning score and better cognitive functioning score. People in the gemcitabine/pemetrexed group had better pain scores. Performance status improvements was seen in 11.4% of gemcitabine/pemetrexed group and 9.4% of gemcitabine group. Weight gain was seen in 10.2% of gemcitabine/pemetrexed group and 5.7% of gemcitabine group
Ueno 2013 – EPA study	Gemcitabine + EPA	8.2 vs 9.7	Not addressed
5FU: fluorouracil; CBR: clinical benefit response; ESPAC: European Study Group for Pancreatic Cancer; EORTC: European Organisation for Research and Treatment of Cancer; FACT‐G: Functional Assessment of Cancer Therapy; FA: folinic acid; KPS: Karnofsky performance status; LASA: linear‐analog self‐assessment indicators; MDASI: MD Anderson Symptom Inventory; QALY: quality‐adjusted life year; QLQ‐C30: quality of life questionnaire for cancer patients; QoL: quality of life; Q‐TWiST: quality‐adjusted time without symptoms or toxicity.

Table 3. Median survival times and quality of life results of gemcitabine combinations versus gemcitabine alone

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Table 4. Median survival times and quality of life results for fluoropyrimidine combinations versus fluoropyrimidine alone

Study	Fluoropyrimidine combination details	Median survival:fluoropyrimidine combination vs fluoropyrimidine alone (months)	Quality of life
Ducreux 2004	5FU + oxaliplatin	3.7 vs 3.4	Not addressed
Kovach 1974	5FU + BCNU	Not stated	Not addressed
Maisey 2002	5FU + MMC	6.5 vs 5.1	EORTC‐QLQ C30 showed that at 24 weeks, global QoL was superior in the combination arm compared to baseline (P = 0.035), and the pain score was also improved (P = 0.048). There was less dyspnoea at 12 weeks in the combination arm when compared to baseline (P = 0.033).
Moertel 1979	5FU + streptozocin	4.5 vs 5.25	Not addressed
5FU: fluorouracil; BCNU: bis‐chloroethylnitrosourea (carmustine); EORTC QLQ‐C30: European Organisation for Research and Treatment of Cancer quality of life questionnaire for cancer patients; MMC: 5FU+doxorubicin + mitomycin C; QoL: quality of life.

Table 4. Median survival times and quality of life results for fluoropyrimidine combinations versus fluoropyrimidine alone

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Table 5. Results of studies addressing unique treatment comparisons

Study	Treatment arms/no. of participants	Survival outcomes	Response rates	Adverse events	Quality of life
Multi‐armed studies
Boeck 2008	Capecitabine/oxaliplatin (n = 61) versus capecitabine/gemcitabine (n = 64) versus modified gemcitabine/oxaliplatin (n = 63)	OS: 8.1 vs 9.0 v 6.9 months PFS 4.2 vs 5.7 v 3.9 months	PR 13% vs 25% vs 13% SbD: 36% vs 39% vs 43%	Haematological AEs more common in the gemcitabine containing arms	Not studied
Cullinan 1985	5FU (n = 50) versus 5FU/doxorubicin (n = 44) versus 5FU/doxorubicin/mitomycin C (n = 50)	Median survival of 22 weeks in all treatment groups	30% vs 30% vs 7.7%	Haematological AEs more common in the 5FU and 5FU/doxorubicin arm, however the subgroup with PC were not reported separately.	Not studied
Cullinan 1990	5FU (n = 64) versus 5FU/cyclophosphamide/methotrexate 'Mallinson Regimen' (n = 61) versus 5FU/doxorubicin/cisplatin 'FAP' (n = 59)	OS: 3.5 vs 4.5 vs 3.5 months respectively PFS: 2.5 vs 2.5 vs 2.5 months	7% vs 21% vs 15%	More AEs reported in the combination arms compared with 5FU alone	Not studied
Kulke 2009	Gemcitabine (fixed dose rate) (n = 64) versus infusional gemcitabine + cisplatin (n = 66) versus infusional gemcitabine + docetaxel (n = 65) versus infusional gemcitabine + irinotecan (n = 60)	OS: 6.4 vs 6.7 vs 6.4 vs 7.1 months, respectively. Time to progression: 3.3 vs 4.5 vs 4.1 vs 4.0 months	14 vs 12.5 vs 12 vs 14%	Neutropenia and fatigue most common AE and same in all groups	Not studied
Other studies
Afchain 2009	Gemcitabine/oxaliplatin (n = 20) vs simplified gemcitabine/oxaliplatin (n = 37)	OS: 3.2 vs 7.6 months PFS: 2.5 vs 4.0 months	PR: 10% vs 27% SbD: 45% vs 43%	Peripheral neuropathy more common in the simplified GemOx arm	Not studied
Bukowski 1983	Mitomycin C/5FU (MF) (n = 73) vs Streptozocin/mitomycin C/5FU (SMF) (n = 72)	OS: 17 vs 18 weeks	PR: 8% v 34%	More gastrointestinal and renal toxicity in the SMF arm	Not studied
Corrie 2017	Standard nab‐paclitaxel and gemcitabine (n = 75) vs sequential nab‐paclitaxel and gemcitabine (n = 71)	OS: 7.9 vs 10.1 months (HR 0.88) PFS: 4.0 vs 5.8 months (HR 0.66)	PR: 33% vs 50% SbD: 28% vs 42%	Neutropenia more common in the sequential arm	QoL score dropped by −12.1 points at 24 weeks in the standard arm vs −2.1 in the sequential arm
Hirao 2011	Gemcitabine 3‐week schedule (n = 45) vs gemcitabine 4‐week schedule (n = 45)	OS: 250 vs 206 days PFS: 114 vs 112 days	17.1% vs 14.2%	Thrombocytopenia more common in the 4‐week schedule	Not studied
Kelsen 1991	Streptozocin/mitomycin C/5FU (SMF) (n = 42) vs cisplatin/ara‐C/caffeine (CAC) (n = 40)	OS: 10 vs 5 months	10% vs 6%	Nausea and vomiting more common in CAC arm.	Not studied
Levi 2004	5FU constant infusion vs 5FU constant infusion/cisplatin versus 5FU chronomodulated infusion vs 5FU chronomodulated infusion/cisplatin (no cisplatin n = 55, with cisplatin n = 52)	OS: 5.4 vs 8.3 months (no cis vs cis) OS: 6.1 vs 6.7 months (continuous vs chronomodulated) PFS: 2.1 vs 3.2 months	Not reported	Cisplatin increased rates of haematological AEs. Chronomodulated regimen increased rates of mucositis	Not studied
Lutz 2005	Gemcitabine + docetaxel (n = 49) vs cisplatin + docetaxel (n = 47)	OS: 7.0 vs 7.5 months PFS: 3.9 vs 2.8 months	19.4% vs 23.5%	Febile neutropenia more common in the cisplatin/docetaxel arm	Not studied
Moertel 1977	Streptozocin + 5FU (n = 40) vs streptozocin + cyclophosphamide (n = 48)	OS: 13 vs 9 weeks	CR: 3 vs 6 PR: 2 vs 0 SbD: 9 vs 9	Haematological AEs more common in the cyclophosphamide arm	Not studied
Reni 2012	Capecitabine + cisplatin + gemcitabine + docetaxel (PDXG) (n = 53) vs capecitabine + cisplatin + gemcitabine + epirubicin (PEXG) (n = 52)	OS: 10.7 vs 11 months PFS: 7.4 vs 7.6 months	CR: 2 vs 4% PR: 58 vs 33%	Neutropenia more common in the PEXG arm	Not studied
Topham 1991	Epirubicin (n = 32) vs 5FU + epirubicin + mitomycin C (n = 30)	1 year survival rates 15.4 vs 23.2%	8% vs 11%	AEs were similar in both arms	Not studied
5FU: fluorouracil; AE: adverse event; CR: complete response; OS: overall survival; PC: pancreatic cancer; PR: partial response; SbD: stable disease.

Table 5. Results of studies addressing unique treatment comparisons

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Comparison 1. Anti‐cancer therapy versus best supportive care

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	4	298	Hazard Ratio (Random, 95% CI)	1.08 [0.88, 1.33]

Comparison 1. Anti‐cancer therapy versus best supportive care

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Comparison 2. Various types of chemotherapy versus gemcitabine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	8		Hazard Ratio (Random, 95% CI)	Subtotals only

1.1 5‐FU	1	126	Hazard Ratio (Random, 95% CI)	1.69 [1.26, 2.27]
1.2 FOLFIRINOX	2	652	Hazard Ratio (Random, 95% CI)	0.51 [0.43, 0.60]
1.3 CO‐101	1	367	Hazard Ratio (Random, 95% CI)	1.07 [0.86, 1.34]
1.4 ZD9331	1	55	Hazard Ratio (Random, 95% CI)	0.86 [0.42, 1.76]
1.5 Fixed dose rate gemcitabine	2	644	Hazard Ratio (Random, 95% CI)	0.79 [0.66, 0.94]
1.6 Exatecan	1	339	Hazard Ratio (Random, 95% CI)	1.27 [0.96, 1.68]
2 Progression‐free survival Show forest plot	5		Hazard Ratio (Random, 95% CI)	Subtotals only

2.1 5‐FU	1	126	Hazard Ratio (Random, 95% CI)	1.47 [1.12, 1.92]
2.2 FOLFIRINOX	2	652	Hazard Ratio (Random, 95% CI)	0.46 [0.38, 0.57]
2.3 ZD9331	1	55	Hazard Ratio (Random, 95% CI)	0.78 [0.46, 1.32]
2.4 Fixed dose rate gemcitabine	1	552	Hazard Ratio (Random, 95% CI)	0.88 [0.77, 1.01]
3 Degradation of QoL at 6 months Show forest plot	2		Hazard Ratio (Random, 95% CI)	0.46 [0.35, 0.61]

4 Response rates Show forest plot	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 5‐FU	1	126	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.71]
4.2 FOLFIRINOX	1	342	Risk Ratio (M‐H, Random, 95% CI)	3.38 [2.01, 5.65]
4.3 CO‐101	1	358	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.43, 1.04]
4.4 ZD9331	1	55	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.04, 4.33]
4.5 Fixed dose rate gemcitabine	2	644	Risk Ratio (M‐H, Random, 95% CI)	1.59 [0.91, 2.79]
4.6 Exatecan (DX‐8951f)	1	276	Risk Ratio (M‐H, Random, 95% CI)	0.10 [0.01, 0.78]
5 Grade 3/4 anaemia Show forest plot	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 5‐FU	1	126	Risk Ratio (M‐H, Random, 95% CI)	0.08 [0.00, 1.34]
5.2 FOLFIRINOX	1	342	Risk Ratio (M‐H, Random, 95% CI)	1.3 [0.59, 2.88]
5.3 CO‐101	1	360	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.59, 1.73]
5.4 ZD9331	1	55	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.01, 6.58]
5.5 Fixed dose rate gemcitabine	2	644	Risk Ratio (M‐H, Random, 95% CI)	1.79 [1.22, 2.63]
5.6 Exatecan	1	330	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.43, 2.34]
6 Grade 3/4 neutropenia Show forest plot	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 5‐FU	1	126	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.06, 0.61]
6.2 FOLFIRINOX	1	342	Risk Ratio (M‐H, Random, 95% CI)	2.14 [1.52, 3.01]
6.3 CO‐101	1	360	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.83, 2.07]
6.4 ZD9331	1	55	Risk Ratio (M‐H, Random, 95% CI)	4.17 [0.52, 33.37]
6.5 Fixed dose rate gemcitabine	2	644	Risk Ratio (M‐H, Random, 95% CI)	1.85 [1.53, 2.23]
6.6 Exatecan	1	330	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.64, 1.55]
7 Grade 3/4 thrombocytopenia Show forest plot	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 5‐FU	1	126	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.02, 1.34]
7.2 FOLFIRINOX	1	342	Risk Ratio (M‐H, Random, 95% CI)	2.5 [0.99, 6.29]
7.3 CO‐101	1	360	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.51, 2.34]
7.4 ZD9331	1	55	Risk Ratio (M‐H, Random, 95% CI)	3.33 [0.40, 27.94]
7.5 Fixed dose rate gemcitabine	2	644	Risk Ratio (M‐H, Random, 95% CI)	2.77 [1.99, 3.86]
7.6 Exatecan	1	330	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.37, 1.54]
8 Grade 3/4 nausea Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

8.1 5‐FU	1	126	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.10, 1.35]
8.2 ZD9331	1	55	Risk Ratio (M‐H, Random, 95% CI)	2.52 [0.11, 59.18]
8.3 Fixed dose rate gemcitabine	2	644	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.94, 2.46]
8.4 Exatecan	1	330	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.52, 5.86]
9 Grade 3/4 diarrhoea Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

9.1 5‐FU	1	126	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.32, 28.07]
9.2 ZD9331	1	55	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.01, 6.58]
9.3 Fixed dose rate gemcitabine	2	644	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.16, 1.23]

Comparison 2. Various types of chemotherapy versus gemcitabine

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Comparison 3. Gemcitabine combinations versus gemcitabine alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	26		Hazard Ratio (Random, 95% CI)	Subtotals only

1.1 Gemcitabine plus platinum agent	6	1140	Hazard Ratio (Random, 95% CI)	0.94 [0.81, 1.08]
1.2 Gemcitabine plus fluoropyrimidine	10	2718	Hazard Ratio (Random, 95% CI)	0.88 [0.81, 0.95]
1.3 Gemcitabine plus topoisomerase inhibitor	3	839	Hazard Ratio (Random, 95% CI)	1.01 [0.87, 1.16]
1.4 Gemcitabine plus taxane	1	861	Hazard Ratio (Random, 95% CI)	0.72 [0.62, 0.84]
1.5 Gemcitabine plus other combinations of chemotherapy	2	166	Hazard Ratio (Random, 95% CI)	0.55 [0.39, 0.79]
1.6 Gemcitabine plus other agent(s)	4	767	Hazard Ratio (Random, 95% CI)	0.79 [0.56, 1.10]
2 Progression‐free survival Show forest plot	18		Hazard Ratio (Random, 95% CI)	Subtotals only

2.1 Gemcitabine plus platinum agent	4	1015	Hazard Ratio (Random, 95% CI)	0.80 [0.68, 0.95]
2.2 Gemcitabine plus fluoropyrimidine	8	2608	Hazard Ratio (Random, 95% CI)	0.79 [0.72, 0.87]
2.3 Gemcitabine plus topoisomerase inhibitor	2	709	Hazard Ratio (Random, 95% CI)	0.91 [0.78, 1.07]
2.4 Gemcitabine plus taxane	1	861	Hazard Ratio (Random, 95% CI)	0.69 [0.58, 0.82]
2.5 Gemcitabine plus other combinations of chemotherapy	2	166	Hazard Ratio (Random, 95% CI)	0.43 [0.30, 0.62]
2.6 Gemcitabine plus other agent(s)	1	76	Hazard Ratio (Random, 95% CI)	1.05 [0.68, 1.62]
3 Response rates Show forest plot	24		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Gemcitabine plus platinum agent	7	1186	Risk Ratio (M‐H, Random, 95% CI)	1.48 [1.11, 1.98]
3.2 Gemcitabine plus fluoropyrimidine	9	2176	Risk Ratio (M‐H, Random, 95% CI)	1.78 [1.29, 2.47]
3.3 Gemcitabine plus topoisomerase inhibitor	3	729	Risk Ratio (M‐H, Random, 95% CI)	1.50 [0.92, 2.46]
3.4 Gemcitabine plus taxane	1	861	Risk Ratio (M‐H, Random, 95% CI)	3.29 [2.24, 4.84]
3.5 Gemcitabane plus other combinations of chemotherapy	1	67	Risk Ratio (M‐H, Random, 95% CI)	1.94 [0.83, 4.56]
3.6 Gemcitabine plus other agent(s)	3	691	Risk Ratio (M‐H, Random, 95% CI)	3.66 [1.04, 12.82]
4 Grade 3/4 anaemia Show forest plot	23		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Gemcitabine plus platinum agent	7	1156	Risk Ratio (M‐H, Random, 95% CI)	1.41 [0.87, 2.31]
4.2 Gemcitabine plus fluoropyrimidine	8	2158	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.84, 1.45]
4.3 Gemcitabine plus topoisomerase inhibitor	3	797	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.72, 1.66]
4.4 Gemcitabine plus taxane	1	793	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.73, 1.52]
4.5 Gemcitabine plus other combinations of chemotherapy	1	67	Risk Ratio (M‐H, Random, 95% CI)	1.94 [0.53, 7.13]
4.6 Gemcitabine plus other agent(s)	3	688	Risk Ratio (M‐H, Random, 95% CI)	3.58 [1.93, 6.62]
5 Grade 3/4 neutropenia Show forest plot	23		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Gemcitabine plus platinum agent	6	961	Risk Ratio (M‐H, Random, 95% CI)	1.34 [0.90, 1.97]
5.2 Gemcitabine plus fluoropyrimidine	9	2177	Risk Ratio (M‐H, Random, 95% CI)	1.53 [1.34, 1.74]
5.3 Gemcitabine plus topoisomerase inhibitor	3	797	Risk Ratio (M‐H, Random, 95% CI)	1.54 [1.04, 2.30]
5.4 Gemcitabine plus taxane	1	793	Risk Ratio (M‐H, Random, 95% CI)	1.42 [1.16, 1.75]
5.5 Gemcitabine plus other combinations of chemotherapy	1	67	Risk Ratio (M‐H, Random, 95% CI)	1.94 [0.65, 5.83]
5.6 Gemcitabine plus other agent(s)	3	688	Risk Ratio (M‐H, Random, 95% CI)	2.02 [0.88, 4.66]
6 Grade 3/4 thrombocytopenia Show forest plot	23		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 Gemcitabine plus platinum agent	6	1110	Risk Ratio (M‐H, Random, 95% CI)	1.96 [1.00, 3.84]
6.2 Gemcitabine plus fluoropyrimidine	9	2177	Risk Ratio (M‐H, Random, 95% CI)	1.48 [1.00, 2.18]
6.3 Gemcitabine plus topoisomerase inhibitor	3	797	Risk Ratio (M‐H, Random, 95% CI)	2.28 [0.97, 5.36]
6.4 Gemcitabine plus taxane	1	793	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.93, 2.07]
6.5 Gemcitabine plus other combinations of chemotherapy	1	67	Risk Ratio (M‐H, Random, 95% CI)	1.94 [0.74, 5.07]
6.6 Gemcitabine plus other agent(s)	3	688	Risk Ratio (M‐H, Random, 95% CI)	1.41 [0.45, 4.39]
7 Grade 3/4 nausea Show forest plot	21		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 Gemcitabine plus platinum agent	6	1110	Risk Ratio (M‐H, Random, 95% CI)	2.28 [1.40, 3.71]
7.2 Gemcitabine plus fluoropyrimidine	7	2075	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.87, 1.84]
7.3 Gemcitabine plus topoisomerase inhibitor	3	797	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.94, 2.55]
7.4 Gemcitabine plus other combinations of chemotherapy	1	67	Risk Ratio (M‐H, Random, 95% CI)	10.69 [0.61, 185.91]
7.5 Gemcitabine plus other agent(s)	4	748	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.48, 3.26]
8 Grade 3/4 diarrhoea Show forest plot	17		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

8.1 Gemcitabine plus platinum agent	6	1110	Risk Ratio (M‐H, Random, 95% CI)	1.48 [0.62, 3.53]
8.2 Gemcitabine plus fluoropyrimidine	8	2087	Risk Ratio (M‐H, Random, 95% CI)	2.16 [1.34, 3.47]
8.3 Gemcitabine plus topoisomerase inhibitor	3	797	Risk Ratio (M‐H, Random, 95% CI)	3.47 [0.74, 16.33]
9 Grade 3/4 neuropathy Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

9.1 Gemcitabine plus taxane	1	793	Risk Ratio (M‐H, Random, 95% CI)	22.35 [7.10, 70.40]
10 Grade 3/4 fatigue Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

10.1 Gemcitabine plus taxane	1	793	Risk Ratio (M‐H, Random, 95% CI)	2.48 [1.63, 3.79]

Comparison 3. Gemcitabine combinations versus gemcitabine alone

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Comparison 4. Fluoropyrimidine combinations versus fluoropyrimidine alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	4	491	Hazard Ratio (Random, 95% CI)	0.84 [0.61, 1.15]

2 Progression‐free survival Show forest plot	2	255	Hazard Ratio (Random, 95% CI)	0.52 [0.19, 1.38]

3 Response rates Show forest plot	4	410	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.52, 2.68]

4 Grade 3/4 anaemia Show forest plot	2	255	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.06, 3.62]

5 Grade 3/4 neutropenia Show forest plot	2	255	Risk Ratio (M‐H, Random, 95% CI)	5.70 [0.73, 44.46]

6 Grade 3/4 thrombocytopenia Show forest plot	2	255	Risk Ratio (M‐H, Random, 95% CI)	1.40 [0.34, 5.80]

7 Grade 3/4 fatigue Show forest plot	1	209	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.58, 1.43]

8 Grade 3/4 nausea Show forest plot	2	255	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.32, 3.53]

9 Grade 3/4 diarrhoea Show forest plot	2	255	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.31, 2.78]

Comparison 4. Fluoropyrimidine combinations versus fluoropyrimidine alone

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