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Inmunoterapia para el carcinoma metastásico de células renales

Appendices

Appendix 1. Cochrane Library (Wiley.com) search strategy

1. MeSH descriptor: [Carcinoma, Renal Cell] explode all trees and with qualifier(s): [Drug therapy ‐ DT, Immunology ‐ IM, Pathology ‐ PA, Prevention & control ‐ PC, Therapy ‐ TH]

2. MeSH descriptor: [von Hippel‐Lindau Disease] explode all trees and with qualifier(s): [Drug therapy ‐ DT, Immunology ‐ IM, Pathology ‐ PA, Prevention & control ‐ PC, Therapy ‐ TH]

3. advance* NEAR (renal OR kidney OR nephron*) NEAR (cancer* OR neoplasm* OR carcinoma* OR tumour* OR tumour*)

4. advance* NEAR (renal or kidney or nephron*) NEXT cell NEAR cancer*

5. metasta* NEAR (renal or kidney or nephron*) NEAR (cancer* or neoplasms* or carcinoma* or tumour* or tumour*)

6. metasta* NEAR (renal or kidney or nephron*) NEXT cell NEAR cancer*

7. local* NEAR advance* NEAR (renal or kidney or nephro*) NEAR (cancer* or neoplasms* or carcinoma* or tumour* or tumour*)

8. local* NEAR advance* NEAR (renal or kidney or nephro*) NEXT cell NEAR cancer*

9. "clear cell type" NEXT/3 carcinom*

10. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9

11. MeSH descriptor: [Immunotherapy, Active] explode all trees

12. MeSH descriptor: [Immunization, Passive] explode all trees

13. MeSH descriptor: [Adoptive Transfer] explode all trees

14. MeSH descriptor: [Cancer Vaccines] explode all trees and with qualifier(s): [Therapeutic use ‐ TU]

15. MeSH descriptor: [Antigens, Neoplasm] explode all trees and with qualifier(s): [Therapeutic use ‐ TU]

16. MeSH descriptor: [Antibodies, Monoclonal] explode all trees and with qualifier(s): [Adverse effects ‐ AE, Therapeutic use ‐ TU]

17. MeSH descriptor: [Hematopoietic Stem Cell Transplantation] explode all trees

18. MeSH descriptor: [Immunomodulation] explode all trees and with qualifier(s): [Drug effects ‐ DE]

19. MeSH descriptor: [Immunologic Factors] explode all trees and with qualifier(s): [Adverse effects ‐ AE, Therapeutic use ‐ TU]

20. MeSH descriptor: [Immunosuppressive Agents] explode all trees and with qualifier(s): [Adverse effects ‐ AE, Therapeutic use ‐ TU]

21. MeSH descriptor: [Superantigens] explode all trees and with qualifier(s): [Adverse effects ‐ AE, Therapeutic use ‐ TU]

22. MeSH descriptor: [Antigens, Neoplasm] explode all trees and with qualifier(s): [Adverse effects ‐ AE, Therapeutic use ‐ TU]

23. vaccin*:ti,ab

24. (immune?ation OR immunotherap* OR immunosuppress* OR immunotox*):ti,ab

25. tum*r NEXT antigen*:ti,ab

26. adjuvants:ti,ab OR adoptive T cell therap*:ti,ab

27. (car or "containment and autonomic regulation") NEXT therapy

28. 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27

29. MeSH descriptor: [Interferon‐alpha] explode all trees and with qualifier(s): [Therapeutic use ‐ TU]

30. MeSH descriptor: [Interleukin‐2] explode all trees and with qualifier(s): [Therapeutic use ‐ TU]

31. MeSH descriptor: [Interleukin‐7] explode all trees and with qualifier(s): [Therapeutic use ‐ TU]

32. MeSH descriptor: [Interleukin‐12] explode all trees and with qualifier(s): [Therapeutic use ‐ TU]

33. MeSH descriptor: [Interleukin‐15] explode all trees and with qualifier(s): [Therapeutic use ‐ TU]

34. MeSH descriptor: [Dendritic Cells] explode all trees

35. MeSH descriptor: [BCG Vaccine] explode all trees

36. MeSH descriptor: [Cytokine‐Induced Killer Cells] explode all trees

37. MeSH descriptor: [Recombinant Proteins] explode all trees

38. vaccin* NEXT/2 (BCG or "Bacillus Calmette Guerin" or Calmette*):ti,ab

39. (DNA or mRNA or cellular or peptid* or protein or genetic) NEXT/2 vaccin*:ti,ab

40. Dendritic cell NEXT/2 bas* NEXT/3 vaccin*:ti,ab

41. immun* NEXT/2 checkpoint:ti,ab

42. Cytotoxic T lymphocyt* or CTL:ti,ab

43. inhibit* NEXT/2 (receptor* or antibod*):ti,ab

44. (humanized or agonistic) NEXT antibod*.ab

45. Anti NEXT/2 (CTLA or "PD‐L1" or "PD‐1" or "sLAG‐3"):ti,ab

46. ("cytotoxic T lymphocytes antigen" or "soluble human LAG‐3 protein"):ti,ab

47. (ipilimumab or tremelimumab or nivolumab or naptumomab or estafenox):ti,ab

48. (IMP321 or IMA901 or AGS‐003 or CMDSC or ABR‐217620 or ANYARA):ti,ab

49. activating receptor*:ti,ab

50. ("denileukin difitox" or reniale or "recombinant human interleukin" or lymphocine):ti,ab

51. "autologous tumour lysate" NEXT/2 "loaded dendritic cells":ti,ab

52. HSPPC NEXT/3 vaccin*:ti,ab

53. mRNA NEXT transfected NEXT dendritic NEXT cell*:ti,ab

54. (co NEXT stimulation) or (co NEXT inhibitation):ti,ab

55. activat* NEXT killer NEXT cell*:ti,ab

56. ("CD4+" or regulat*) NEXT/3 "T" NEXT cell*:ti,ab

57. myeloid NEXT deriv* NEXT/3 suppressor* NEXT cell*:ti,ab

58. (tum*r NEXT associat* NEXT macrophag*) or TAM:ti,ab

59. "CpG" NEXT oligonucleotid*:ti,ab

60. 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59

61. 28 or 60

62. 10 and 61

Appendix 2. MEDLINE (Ovid) search strategy

1. exp Carcinoma, Renal Cell/dt, pa, th, im, pc [Drug Therapy, Pathology, Therapy, Immunology, Prevention & Control]

2. von Hippel‐Lindau Disease/dt, pa, th, im, pc [Drug Therapy, Pathology, Therapy, Immunology, Prevention & Control]

3. (advance* adj6 (renal OR kidney OR nephron$) adj6 (cancer$ OR neoplasms$ OR carcinoma$ OR tumour$ OR tumour$)).mp

4. (advance* adj6 (renal or kidney or nephron$) adj cell adj6 cancer$).mp.

5. (metasta* adj6 (renal or kidney or nephron$) adj6 (cancer$ or neoplasms$ or carcinoma$ or tumour$ or tumour$)).mp

6. (metasta* adj6 (renal or kidney or nephron$) adj cell adj6 cancer$).mp

7. (local* adj6 advance* adj6 (renal or kidney or nephro*) adj6 (cancer$ or neoplasms$ or carcinoma$ or tumour$ or tumour$)).mp

8. (local* adj6 advance* adj6 (renal or kidney or nephro*) adj cell adj6 cancer$).mp

9. ("clear cell type" adj3 carcinom$).mp

10. or/1‐9

11. exp Immunotherapy, Active /ae, tu [therapeutic use]

12. Immunization, Passive/ae, tu [Adverse Effects, Therapeutic Use]

13. Adoptive Transfer/ or adoptive T cell therap$.ti,ab

14. Cancer Vaccines /ae, tu

15. exp Antigens, Neoplasm /ae, tu

16. exp Antibodies, Monoclonal /ae, tu

17. Hematopoietic Stem Cell Transplantation

18. exp Immunomodulation/de [Drug Effects]

19. Immunologic Factors/ ae, tu

20. Immunosuppressive Agents/ae, tu

21. exp Superantigens/ae, tu

22. exp Antigens, Neoplasm/ae, tu

23. vaccin$.ti,ab

24. (immuni#ation OR immunotherap$ OR immunosuppress$ OR immunotox$).ti,ab

25. ((tumour or tumour) adj antigen$).ti,ab

26. Adjuvants.ti,ab

27. ((car or "containment and autonomic regulation") adj therapy).mp

28. or/11‐27

29. Interferon‐alpha/tu OR Interleukin‐2/tu OR Interleukin‐7/tu OR Exp Interleukin‐12/tu OR Interleukin‐15/tu

30. Exp Dendritic Cells/ OR BCG vaccine/

31. exp Cytokine‐Induced Killer Cells/de

32. exp Recombinant Proteins/tu

33. (vaccin$ adj2 (BCG or "Bacillus Calmette Guerin" or Calmette$)).ti,ab

34. ((DNA or mRNA or cellular or peptid$ or protein or genetic) adj2 vaccin$).ti,ab

35. (Dendritic cell adj2 bas$ adj3 vaccin$).ti,ab

36. (immun$ adj2 checkpoint).ti,ab

37. (Cytotoxic T lymphocyt$ or CTL).ti,ab

38. (inhibit$ adj2 (receptor$ or antibod$)).ti,ab

39. (humanized or agonistic) adj antibod$.ab

40. (Anti adj2 (CTLA or "PD‐L1" or "PD‐1" or "sLAG‐3")).ti,ab

41. ("cytotoxic T lymphocytes antigen" or "soluble human LAG‐3 protein").ti,ab

42. (ipilimumab or tremelimumab or nivolumab or naptumomab or estafenox).ti,ab

43. (IMP321 or IMA901 or AGS‐003 or CMDSC or ABR‐217620 or ANYARA).ti,ab

44. (activating receptor$).ti,ab

45. ("denileukin difitox" or reniale or "recombinant human interleukin" or lymphocine).ti,ab

46. ("autologous tumour lysate" adj2 "loaded dendritic cells").ti,ab

47. (HSPPC adj3 vaccin$).ti,ab

48. (mRNA transfected dendritic cell$).ti,ab

49. ((co adj stimulation) or (co adj inhibitation)).ti,ab

50. (activat$ adj killer adj cell$).ti,ab

51. ((CD4+ or regulat$) adj3 T adj cell$).ti,ab

52. (myeloid adj deriv$ adj3 suppressor$ adj cell$).ti,ab

53. ((tumour adj associat$ macrophag$) or (tumour adj associat$ macrophag$) or TAM).ti,ab

54. (CpG adj oligonucleotid$).ti,ab

55. or/29‐54

56. 28 or 55

57. randomised controlled trial.pt.

58. controlled clinical trial.pt.

59. randomised.ab.

60. placebo.ab.

61. drug therapy.fs.

62. randomly.ab.

63. trial.ab.

64. groups.ab.

65. or/57‐64

66. exp animals/ not humans/

67. 65 not 66

68. 10 and 56 and 67

Appendix 3. Embase (Ovid) search strategy

1 kidney carcinoma/

2 von Hippel Lindau disease/

3 (advance$ adj6 (renal or kidney or nephron$) adj6 (cancer$ or neoplasms$ or carcinoma$ or tumour$ or tumour$)).mp.

4 (advance$ adj6 (renal or kidney or nephron$) adj cell adj6 cancer$).mp.

5 (metasta$ adj6 (renal or kidney or nephron$) adj6 (cancer$ or neoplasms$ or carcinoma$ or tumour$ or tumour$)).mp.

6 (metasta$ adj6 (renal or kidney or nephron$) adj cell adj6 cancer$).mp.

7 (local$ adj6 advance$ adj6 (renal or kidney or nephro$) adj6 (cancer$ or neoplasms$ or carcinoma$ or tumour$ or tumour$)).mp.

8 (local$ adj6 advance$ adj6 (renal or kidney or nephro$) adj cell adj6 cancer$).mp.

9 ("clear cell type" adj3 carcinom$).mp.

10 or/1‐9

11 exp immunotherapy/

12 exp passive immunization/

13 adoptive transfer.ti,ab.

14 adoptive t cell therap*.ti,ab.

15 cancer vaccine/

16 exp tumour antigen/

17 exp monoclonal antibody/

18 exp hematopoietic stem cell transplantation/

19 immunomodulation/

20 immunologic factor/

21 exp immunosuppressive agent/

22 superantigen/

23 alpha interferon/

24 interleukin 2/

25 interleukin 7/

26 interleukin 12/

27 interleukin 15/

28 exp dendritic cell/

29 BCG vaccine/

30 vaccin$.ti,ab.

31 (immuni#ation or immunotherap$ or immunosuppress$ or immunotox$).ti,ab.

32 ((tumour or tumour) adj antigen$).ti,ab.

33 Adjuvants.ti,ab.

34 ((car or "containment and autonomic regulation") adj therapy).mp.

35 (vaccin$ adj2 (BCG or "Bacillus Calmette Guerin" or Calmette$)).ti,ab.

36 ((DNA or mRNA or cellular or peptid$ or protein or genetic) adj2 vaccin$).ti,ab.

37 (Dendritic cell adj2 bas$ adj3 vaccin$).ti,ab.

38 (immun$ adj2 checkpoint).ti,ab.

39 (Cytotoxic T lymphocyt$ or CTL).ti,ab.

40 (inhibit$ adj2 (receptor$ or antibod$)).ti,ab.

41 ((humanized or agonistic) adj antibod$).ab.

42 (Anti adj2 (CTLA or "PD‐L1" or "PD‐1" or "sLAG‐3")).ti,ab.

43 ("cytotoxic T lymphocytes antigen" or "soluble human LAG‐3 protein").ti,ab.

44 (ipilimumab or tremelimumab or nivolumab or naptumomab or estafenox).ti,ab.

45 (IMP321 or IMA901 or AGS‐003 or CMDSC or ABR‐217620 or ANYARA).ti,ab.

46 activating receptor$.ti,ab.

47 ("denileukin difitox" or reniale or "recombinant human interleukin" or lymphocine).ti,ab.

48 ("autologous tumour lysate" adj2 "loaded dendritic cells").ti,ab.

49 (HSPPC adj3 vaccin$).ti,ab.

50 mRNA transfected dendritic cell$.ti,ab.

51 ((co adj stimulation) or (co adj inhibitation)).ti,ab.

52 (activat$ adj killer adj cell$).ti,ab.

53 ((CD4+ or regulat$) adj3 T adj cell$).ti,ab.

54 (myeloid adj deriv$ adj3 suppressor$ adj cell$).ti,ab.

55 ((tumour adj associat$ macrophag$) or (tumour adj associat$ macrophag$) or TAM).ti,ab.

56 (CpG adj oligonucleotid$).ti,ab.

57 or/11‐56

58 10 and 57

59 Crossover Procedure/

60 double‐blind procedure/

61 randomised controlled trial/

62 single‐blind procedure/

63 (random$ or factorial$ or crossover$ or cross over$ or placebo$ or assign$ or allocat$ or volunteer$).mp.

64 ((doubl$ or singl$) adj blind$).mp.

65 or/59‐64

66 exp animal/ not human.sh.

67 65 not 66

68 58 and 67

Appendix 4. ClinicalTrials.gov search strategy

Search strategies in Advanced Search

Search 1:

Interventions: Immunotherapy OR Immunization OR Cancer Vaccines OR tumour antigen OR monoclonal antibody OR hematopoietic stem cell transplantation OR immunosuppressive agent OR superantigen OR adoptive transfer

Conditions: metastatic renal cell carcinoma

Search 2:

Interventions: tumour‐associated peptides OR interferon alpha OR interleukin 2 OR interleukin 7 OR interleukin 12 OR interleukin 15 OR dendritic cell OR BCG vaccine OR DNA vaccine OR mRNA vaccine OR cellular vaccine

Conditions: metastatic renal cell carcinoma

Search 3:

Interventions: peptide vaccine OR peptid vaccine OR protein vaccine OR genetic vaccine OR IMP321 OR IMA901 OR AGS‐003 OR CMDSC OR ABR‐217620 OR ANYARA

Conditions: metastatic renal cell carcinoma

Search 4:

Interventions: immune checkpoint inhibitor OR CTLA OR PD‐L1 OR PD‐1 OR sLAG‐3 OR cytotoxic T lymphocytes antigen OR soluble human LAG‐3 protein OR ipilimumab OR tremelimumab OR nivolumab OR atezolizumab OR pembrolizumab OR pidilizumab OR durvalumab

Conditions: metastatic renal cell carcinoma

Appendix 5. WHO ICTRP search strategy

In the Condition:

metastatic renal cell carcinoma

In the Intervention:

Immunotherapy OR Immunization OR Cancer Vaccines OR tumour antigen OR monoclonal antibody OR hematopoietic stem cell transplantation OR immunosuppressive agent OR superantigen OR tumour‐associated peptides OR interferon alpha OR interleukin 2 OR interleukin 7 OR interleukin 12 OR interleukin 15 OR dendritic cell OR BCG vaccine OR DNA vaccine OR mRNA vaccine OR cellular vaccine OR peptide vaccine OR peptid vaccine OR protein vaccine OR genetic vaccine OR IMP321 OR IMA901 OR AGS‐003 OR CMDSC OR ABR‐217620 OR ANYARA OR adoptive transfer OR immune checkpoint inhibitor OR CTLA OR PD‐L1 OR PD‐1 OR sLAG‐3 OR cytotoxic T lymphocytes antigen OR soluble human LAG‐3 protein OR ipilimumab OR tremelimumab OR nivolumab OR atezolizumab OR pembrolizumab OR pidilizumab OR durvalumab

Appendix 6. EORTC search strategy

We browsed the website www.eortc.be/protoc/listprot.asp?kind=sites&site=24 and screened all trials by tumour site (kidney cancer).

Appendix 7. Web of Science Core Collection ‐ Meeting Abstracts search strategy

Search in "TOPIC" field:

"metastatic renal cell carcinoma" OR (metastatic NEAR/2 (renal or kidney or nephron*) NEAR/2 (cancer* or neoplasms* or carcinoma* or tumour* or tumour*))

AND

Immunotherapy OR Immunization OR Cancer Vaccines OR adoptive transfer OR tumour antigen OR monoclonal antibody OR hematopoietic stem cell transplantation OR immunosuppressive agent OR superantigen OR tumour‐associated peptides OR interferon alpha OR interleukin 2 OR interleukin 7 OR interleukin 12 OR interleukin 15 OR dendritic cell OR BCG vaccine OR DNA vaccine OR mRNA vaccine OR cellular vaccine OR peptide vaccine OR peptid vaccine OR protein vaccine OR genetic vaccine OR IMP321 OR IMA901 OR AGS‐003 OR CMDSC OR ABR‐217620 OR ANYARA

Refine to Document Type: Meeting Abstract

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

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

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 3

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

Forest plot of comparison: 1 Interferon‐α (IFN‐α) alone versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma, outcome: 1.1 1‐year mortality.
Figures and Tables -
Figure 4

Forest plot of comparison: 1 Interferon‐α (IFN‐α) alone versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma, outcome: 1.1 1‐year mortality.

Forest plot of comparison: 3 Interferon (IFN‐α) alone versus IFN‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma, outcome: 3.1 1‐year mortality.
Figures and Tables -
Figure 5

Forest plot of comparison: 3 Interferon (IFN‐α) alone versus IFN‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma, outcome: 3.1 1‐year mortality.

Forest plot of comparison: 5 Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma, outcome: 5.1 1‐year mortality.
Figures and Tables -
Figure 6

Forest plot of comparison: 5 Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma, outcome: 5.1 1‐year mortality.

Comparison 1 Interferon‐α (IFN‐α) alone versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 1 1‐year mortality.
Figures and Tables -
Analysis 1.1

Comparison 1 Interferon‐α (IFN‐α) alone versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 1 1‐year mortality.

Comparison 1 Interferon‐α (IFN‐α) alone versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 2 Overall survival.
Figures and Tables -
Analysis 1.2

Comparison 1 Interferon‐α (IFN‐α) alone versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 2 Overall survival.

Comparison 1 Interferon‐α (IFN‐α) alone versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 3 Quality of life.
Figures and Tables -
Analysis 1.3

Comparison 1 Interferon‐α (IFN‐α) alone versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 3 Quality of life.

Comparison 1 Interferon‐α (IFN‐α) alone versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 4 Adverse events (grade ≥ 3).
Figures and Tables -
Analysis 1.4

Comparison 1 Interferon‐α (IFN‐α) alone versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 4 Adverse events (grade ≥ 3).

Comparison 1 Interferon‐α (IFN‐α) alone versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 5 Progression‐free survival.
Figures and Tables -
Analysis 1.5

Comparison 1 Interferon‐α (IFN‐α) alone versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 5 Progression‐free survival.

Comparison 1 Interferon‐α (IFN‐α) alone versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 6 Tumour remission.
Figures and Tables -
Analysis 1.6

Comparison 1 Interferon‐α (IFN‐α) alone versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 6 Tumour remission.

Comparison 2 Interferon‐α (IFN‐α) combined with targeted therapy versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma, Outcome 1 1‐year mortality.
Figures and Tables -
Analysis 2.1

Comparison 2 Interferon‐α (IFN‐α) combined with targeted therapy versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma, Outcome 1 1‐year mortality.

Comparison 2 Interferon‐α (IFN‐α) combined with targeted therapy versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma, Outcome 2 Overall survival.
Figures and Tables -
Analysis 2.2

Comparison 2 Interferon‐α (IFN‐α) combined with targeted therapy versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma, Outcome 2 Overall survival.

Comparison 2 Interferon‐α (IFN‐α) combined with targeted therapy versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma, Outcome 3 Adverse events (grade ≥ 3).
Figures and Tables -
Analysis 2.3

Comparison 2 Interferon‐α (IFN‐α) combined with targeted therapy versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma, Outcome 3 Adverse events (grade ≥ 3).

Comparison 2 Interferon‐α (IFN‐α) combined with targeted therapy versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma, Outcome 4 Progression‐free survival.
Figures and Tables -
Analysis 2.4

Comparison 2 Interferon‐α (IFN‐α) combined with targeted therapy versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma, Outcome 4 Progression‐free survival.

Comparison 2 Interferon‐α (IFN‐α) combined with targeted therapy versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma, Outcome 5 Tumour remission.
Figures and Tables -
Analysis 2.5

Comparison 2 Interferon‐α (IFN‐α) combined with targeted therapy versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma, Outcome 5 Tumour remission.

Comparison 3 Interferon (IFN‐α) alone versus IFN‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma, Outcome 1 1‐year mortality.
Figures and Tables -
Analysis 3.1

Comparison 3 Interferon (IFN‐α) alone versus IFN‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma, Outcome 1 1‐year mortality.

Comparison 3 Interferon (IFN‐α) alone versus IFN‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma, Outcome 2 Overall survival.
Figures and Tables -
Analysis 3.2

Comparison 3 Interferon (IFN‐α) alone versus IFN‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma, Outcome 2 Overall survival.

Comparison 3 Interferon (IFN‐α) alone versus IFN‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma, Outcome 3 Adverse events (grade ≥ 3).
Figures and Tables -
Analysis 3.3

Comparison 3 Interferon (IFN‐α) alone versus IFN‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma, Outcome 3 Adverse events (grade ≥ 3).

Comparison 3 Interferon (IFN‐α) alone versus IFN‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma, Outcome 4 Progression‐free survival.
Figures and Tables -
Analysis 3.4

Comparison 3 Interferon (IFN‐α) alone versus IFN‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma, Outcome 4 Progression‐free survival.

Comparison 3 Interferon (IFN‐α) alone versus IFN‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma, Outcome 5 Tumour remission.
Figures and Tables -
Analysis 3.5

Comparison 3 Interferon (IFN‐α) alone versus IFN‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma, Outcome 5 Tumour remission.

Comparison 4 Interferon‐α (IFN‐α) plus bevacizumab versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 1 1‐year mortality.
Figures and Tables -
Analysis 4.1

Comparison 4 Interferon‐α (IFN‐α) plus bevacizumab versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 1 1‐year mortality.

Comparison 4 Interferon‐α (IFN‐α) plus bevacizumab versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 2 Adverse events (grade ≥ 3).
Figures and Tables -
Analysis 4.2

Comparison 4 Interferon‐α (IFN‐α) plus bevacizumab versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 2 Adverse events (grade ≥ 3).

Comparison 4 Interferon‐α (IFN‐α) plus bevacizumab versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 3 Progression‐free survival.
Figures and Tables -
Analysis 4.3

Comparison 4 Interferon‐α (IFN‐α) plus bevacizumab versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 3 Progression‐free survival.

Comparison 4 Interferon‐α (IFN‐α) plus bevacizumab versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 4 Tumour remission.
Figures and Tables -
Analysis 4.4

Comparison 4 Interferon‐α (IFN‐α) plus bevacizumab versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 4 Tumour remission.

Comparison 5 Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 1 1‐year mortality.
Figures and Tables -
Analysis 5.1

Comparison 5 Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 1 1‐year mortality.

Comparison 5 Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 2 Overall survival.
Figures and Tables -
Analysis 5.2

Comparison 5 Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 2 Overall survival.

Comparison 5 Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 3 Adverse events (grade ≥ 3).
Figures and Tables -
Analysis 5.3

Comparison 5 Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 3 Adverse events (grade ≥ 3).

Comparison 5 Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 4 Progression‐free survival.
Figures and Tables -
Analysis 5.4

Comparison 5 Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 4 Progression‐free survival.

Comparison 5 Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 5 Tumour remission.
Figures and Tables -
Analysis 5.5

Comparison 5 Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma, Outcome 5 Tumour remission.

Comparison 6 Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma, Outcome 1 1‐year mortality.
Figures and Tables -
Analysis 6.1

Comparison 6 Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma, Outcome 1 1‐year mortality.

Comparison 6 Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma, Outcome 2 Overall survival.
Figures and Tables -
Analysis 6.2

Comparison 6 Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma, Outcome 2 Overall survival.

Comparison 6 Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma, Outcome 3 Quality of life.
Figures and Tables -
Analysis 6.3

Comparison 6 Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma, Outcome 3 Quality of life.

Comparison 6 Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma, Outcome 4 Adverse events (grade ≥ 3).
Figures and Tables -
Analysis 6.4

Comparison 6 Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma, Outcome 4 Adverse events (grade ≥ 3).

Comparison 6 Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma, Outcome 5 Progression‐free survival.
Figures and Tables -
Analysis 6.5

Comparison 6 Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma, Outcome 5 Progression‐free survival.

Comparison 6 Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma, Outcome 6 Tumour remission.
Figures and Tables -
Analysis 6.6

Comparison 6 Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma, Outcome 6 Tumour remission.

Summary of findings for the main comparison. Interferon‐α alone versus standard targeted therapies (sunitinib or temsirolimus) in first‐line therapy of metastatic renal cell carcinoma

IFN‐α alone versus standard targeted therapy for mRCC

Patient population: previously untreated patients with mRCC

Settings: phase III, international, multicentre, open‐label

Intervention: IFN‐α alone

Comparison: standard targeted therapy (sunitinib or temsirolimus)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Risk with standard targeted therapy

Risk difference with IFN‐α alone (95% CI)

1‐year mortality
Follow‐up: 1 to 36 months

Lowa

RR 1.3
(1.13 to 1.51)

1166
(2 studies)

⊕⊕⊕⊝
Moderate1

150 per 1000

45 more per 1000
(from 20 more to 76 more)

Moderatea

280 per 1000

84 more per 1000
(from 36 more to 143 more)

Higha

550 per 1000

165 more per 1000
(from 71 more to 280 more)

QoL
FACT‐G
Follow‐up: median 17 weeks

The mean QoL in the control group was
82.3 pointsb

MD 5.58 lower
(7.25 to 3.91 lower)

730
(1 study)

⊕⊕⊝⊝
Low2,3

QoL
FKSI‐15
Follow‐up: median 17 weeks

The mean QoL in the control group was
45.3 pointsb

MD 3.27 lower

(4.18 to 2.36 lower)

730
(1 study)

⊕⊕⊝⊝
Low2,3

QoL
FKSI‐DRS
Follow‐up: median 17 weeks

The mean QoL in the control group was
29.4 pointsb

MD 1.98 lower

(2.51 to 1.46 lower)

730
(1 study)

⊕⊕⊝⊝
Low2,3

QoL
EQ‐5D
Follow‐up: range 12 to 17 weeks

The mean QoL in the control group was
0.711pointsb

MD 0.06 lower

(0.12 lower to 0 higher)

1002

(2 studies)

⊕⊕⊝⊝
Low2,3

QoL
EQ‐VAS
Follow‐up: range 12 to 17 weeks

The mean QoL in the control groups was
70.4pointsb

MD 4.68 lower

(6.53 to 2.83 lower)

1002

(2 studies)

⊕⊕⊝⊝
Low2,3

Adverse events (grade ≥ 3)
Follow‐up: 14 to 36 months

668 per 1000

114 more per 1000
(from 20 more to 214 more)

RR 1.17
(1.03 to 1.32)

408
(1 study)

⊕⊕⊝⊝
Low2,3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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; EQ‐5D: EuroQol 5‐Dimension; EQ‐VAS: EuroQol Visual Analogue Scale; FACT‐G: Functional Assessment of Cancer Therapy ‐ General; FKSI‐15: FACT‐Kidney Symptom Index; FKSI‐DRS: FACT‐Kidney Symptom Index Disease Related Symptoms; IFN‐α: interferon‐α; MD: mean difference; mRCC: metastatic renal cell carcinoma; QoL: quality of life; 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.

1 Downgraded for selection bias and performance bias due to cross‐over.
2 Downgraded for performance and detection bias.
3 Downgraded for imprecision due to wide confidence intervals; clinical action would differ between lower and upper boundary of the confidence interval.
a Moderate risk of 1‐year mortality from the SEER (Surveillance, Epidemiology, and End Results) Cancer Statistics Review (Howlader 2015), low risk from participants with favourable risk in Rini 2015, high risk from Hudes 2007.
b Mean postbaseline value on treatment.

Figures and Tables -
Summary of findings for the main comparison. Interferon‐α alone versus standard targeted therapies (sunitinib or temsirolimus) in first‐line therapy of metastatic renal cell carcinoma
Summary of findings 2. Interferon‐α combined with targeted therapies versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma

IFN‐α alone or combined with targeted therapy compared to standard targeted therapy in first‐line therapy of mRCC

Patient population: previously untreated patients with mRCC

Setting: phase III, international, multicentre, open‐label

Intervention: IFN‐α combined with targeted therapy

Comparison: standard targeted therapy (temsirolimus)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Risk with standard targeted therapy

Risk difference with IFN‐α combined with targeted therapy (95% CI)

1‐year mortality
Follow‐up: 14‐36 months

Lowa

RR 1.13
(0.95 to 1.34)

419
(1 study)

⊕⊕⊕⊝
Moderate1

150 per 1000

20 more per 1000
(from 8 fewer to 51 more)

Moderatea

280 per 1000

36 more per 1000
(from 14 fewer to 95 more)

Higha

550 per 1000

71 more per 1000
(from 28 fewer to 187 more)

Quality of life

No evidence available

Adverse events (grade ≥ 3)
Follow‐up: 14 to 36 months

668 per 1000

200 more per 1000
(from 114 more to 301 more)

RR 1.30
(1.17 to 1.45)

416
(1 study)

⊕⊕⊝⊝
Low1,2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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; IFN‐α: interferon‐α; mRCC: metastatic renal cell carcinoma; 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.

1 Downgraded for imprecision due to wide confidence intervals; clinical action would differ between lower and upper boundary of the confidence interval.
2 Downgraded for performance and detection bias.
a Moderate risk of 1‐year mortality from the SEER Cancer Statistics Review (Howlader 2015), low risk from participants with favourable risk in Rini 2015, high risk from Hudes 2007.

Figures and Tables -
Summary of findings 2. Interferon‐α combined with targeted therapies versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma
Summary of findings 3. Interferon‐α alone versus interferon‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma

IFN‐α alone versus IFN‐α + bevacizumab in first‐line therapy of mRCC

Patient population: previously untreated patient with mRCC

Setting: phase III, international, multicentre, Escudier 2007: double‐blind, placebo‐controlled; Rini 2010: open‐label

Intervention: IFN‐α alone

Comparison: IFN‐α alone + bevacizumab

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Risk with standard therapy (IFN‐α + bevacizumab)

Risk difference with IFN‐α alone (95% CI)

1‐year mortality
Follow‐up: 13.3 to 22 months

Low

RR 1.17
(1.00 to 1.36)

1381
(2 studies)

⊕⊕⊝⊝
Low1,2

150 per 1000

25 more per 1000
(from 0 more to 54 more)

Moderate

280 per 1000

48 more per 1000
(from 0 more to 101 more)

High

550 per 1000

93 more per 1000
(from 0 more to 198 more)

Quality of life

No evidence available

Adverse events (grade ≥ 3)

Follow‐up: up to 28 days after last dose to 65 months

705 per 1000

162 fewer per 1000
(from 113 fewer to 205 fewer)

RR 0.77
(0.71 to 0.84)

1350
(2 studies)

⊕⊕⊕⊝
Moderate3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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; IFN‐α: interferon‐α; mRCC: metastatic renal cell carcinoma; 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.

1 Downgraded for selection bias and performance bias due to substantial cross‐over.
2 Downgraded for imprecision due to wide confidence intervals; clinical action would differ between lower and upper boundary of the confidence interval.
3 Downgraded for performance and detection bias.

Figures and Tables -
Summary of findings 3. Interferon‐α alone versus interferon‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma
Summary of findings 4. Interferon‐α plus bevacizumab versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma

IFN‐α + bevacizumab versus targeted therapies in first‐line therapy of mRCC

Patient population: previously untreated patients with mRCC

Setting: phase II, national (France), multicentre, open‐label

Intervention: IFN‐α + bevacizumab

Comparison: standard targeted therapies (sunitinib)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Risk with standard targeted therapies

Risk difference with IFN‐α + bevacizumab (95% CI)

1‐year mortality
median

Follow‐up: 23.2 months

Lowa

RR 0.37
(0.13 to 1.08)

83
(1 study)

⊕⊕⊝⊝
Low1,2

150 per 1000

95 fewer per 1000
(131 fewer to 12 more)

Moderatea

280 per 1000

176 fewer per 1000
(from 244 fewer to 22 more)

Higha

550 per 1000

347 fewer per 1000
(from 479 fewer to 44 more)

Quality of life

No evidence available

Adverse events (grade ≥ 3)

Follow‐up: 48 weeks

595 per 1000

107 more per 1000
(from 89 fewer to 369 more)

RR 1.18
(0.85 to 1.62)

82
(1 study)

⊕⊕⊝⊝
Low2,3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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; mRCC: metastatic renal cell carcinoma; 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.

1 Downgraded for reporting and performance bias due to differences in second‐line treatment.
2 Downgraded for imprecision due to wide confidence intervals; clinical action would differ between lower and upper boundary of the confidence interval.
3 Downgraded for performance and detection bias.
a Moderate risk of 1‐year mortality from the SEER Cancer Statistics Review (Howlader 2015), low risk from participants with favourable risk in Rini 2015, high risk from Hudes 2007.

Figures and Tables -
Summary of findings 4. Interferon‐α plus bevacizumab versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma
Summary of findings 5. Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma

Vaccine treatment versus standard therapies in first‐line therapy of mRCC

Patient population: previously untreated patients with mRCC

Setting: phase III, international, multicentre, double‐blind, placebo‐controlled (Amato 2010), open‐label (Rini 2015)

Intervention: vaccine treatment (MVA‐5T4 or IMA0901)

Comparison: placebo and standard therapies (IL‐2, IFN‐α and sunitinib)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Risk with standard therapies

Risk difference with vaccine treatment (95% CI)

1‐year mortality
Follow‐up: 12 to 48 months

Lowa

RR 1.10
(0.91 to 1.32)

1034
(2 studies)

⊕⊕⊝⊝
Low1,2,3

150 per 1000

15 more per 1000
(from 13 fewer to 48 more)

Moderatea

280 per 1000

28 more per 1000
(from 25 fewer to 90 more)

Higha

550 per 1000

55 more per 1000
(from 49 fewer to 176 more)

Quality of life

No evidence available

Adverse events (grade ≥ 3)

Follow‐up: not reported

241 per 1000

39 more per 1000
(from 7 fewer to 94 more)

RR 1.16
(0.97 to 1.39)

1065
(2 studies)

⊕⊕⊝⊝
Low3,4,5

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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; mRCC: metastatic renal cell carcinoma; 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.

1 Not downgraded for performance bias, borderline decision due to second‐line therapies in one study.
2 Downgraded for indirectness due to non‐standard therapies (low‐dose interleukin‐2, IFN‐α) in 75% participants of both treatment arms.
3 Downgraded for imprecision due to wide confidence intervals; clinical action would differ between lower and upper boundary of the confidence interval.
4 Downgraded for performance and detection bias.
5 Not downgraded for indirectness, borderline decision due to non‐standard therapies in both treatment arms.
a Moderate risk of 1‐year mortality from the SEER Cancer Statistics Review (Howlader 2015), low risk from participants with favourable risk in Rini 2015, high risk from Hudes 2007.

Figures and Tables -
Summary of findings 5. Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma
Summary of findings 6. Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma

Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with mRCC

Patient population: previously treated patients with mRCC

Setting: phase III, international, multicentre, open‐label

Intervention: targeted immunotherapy (nivolumab) alone

Comparison: standard targeted therapies (everolimus)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Risk with standard targeted therapies

Risk difference with targeted immunotherapy alone (95% CI)

1‐year mortality
Follow‐up: > 14 months

341 per 1000

102 fewer per 1000
(from 44 fewer to 150 fewer)

RR 0.70
(0.56 to 0.87)

821
(1 study)

⊕⊕⊕⊝
Moderate1

Quality of life: Clinically relevant improvement in FKSI‐DRS
Follow‐up: 1 to 104 weeks

367 per 1000

187 more per 1000

(from 103 more to 287 more)

RR 1.51 (1.28 to 1.78)

704
(1 study)

⊕⊕⊕⊝
Moderate2

Quality of life: clinically relevant improvement in EQ‐5D VAS
Follow‐up: 1 to 104 weeks

391 per 1000

145 more per 1000

(from 63 more to 238 more)

RR 1.37 (1.16‐1.61)

703

(1 study)

⊕⊕⊕⊝
Moderate2

Adverse events (grade ≥ 3)

365 per 1000

179 fewer per 1000
(from 128 fewer to 219 fewer)

RR 0.51
(0.40 to 0.65)

803
(1 study)

⊕⊕⊕⊝
Moderate2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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; EQ‐5D VAS: EuroQol 5‐Dimension Visual Analogue Scale; FKSI‐DRS: FACT‐Kidney Symptom Index Disease Related Symptoms; mRCC: metastatic renal cell carcinoma; 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.

1 Downgraded for performance bias due to cross‐over.
2 Downgraded for performance and detection bias.

Figures and Tables -
Summary of findings 6. Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma
Table 1. Overall survival

Study ID

Comparison (group 1 vs group 0)

Median OS (95% CI) (months)

1‐year mortality

Comments

Group 1

Group 0

Group 1

Group 0

Hudes 2007

1 (IFN‐α alone vs standard targeted therapies)

7.3 (6.1 to 8.8)

10.9 (8.6 to 12.7)

70%

53%

From curves.

Motzer 2007

21.8 (17.9 to 26.9)

26.4 (23.0 to 32.9)

12.3%

10.1%

Numbers reported.

Hudes 2007

2 (IFN‐α + targeted therapies vs standard targeted therapies)

8.4 (6.6 to 10.3)

10.9 (8.6 to 12.7)

60%

53%

From curves.

Escudier 2007

3 (IFN‐α alone vs IFN‐α + bevacizumab)

21.3

23.3

32%

26%

From curves.

Rini 2010

17.4 (14.4 to 20.0)

18.3 (16.5 to 22.5)

39%

34%

From curves with numbers and censoring marks.

Negrier 2011

4 (IFN‐α + bevacizumab vs standard targeted therapies)

Not reported

Not reported

10%

26%

Reported.

Amato 2010

5 (Vaccine treatment vs standard therapies)

19.2

20.1

35%

33%

From curves with censoring.

Rini 2015

33.1

Not reached

17%

22%

Numbers reported.

Motzer 2015a

6 (Targeted immunotherapy alone vs targeted standard therapy)

25.0 (21.8 to NE)

19.6 (17.6 to 23.1)

24%

34%

From curves with numbers with censoring marks.

CI: confidence interval; IFN‐α: interferon‐α; NE: not estimable; OS: overall survival.

Figures and Tables -
Table 1. Overall survival
Table 2. Overall survival subgroups

Comparison (group 1 vs group 0)

Study

Subgroup

Sample size

Treatment effects (95% CI) or P values

1 (IFN‐α alone vs standard targeted therapies)

Hudes 2007

Prior nephrectomy

278

HR 1.2 (0.9 to 1.6)

Motzer 2007

Prior nephrectomy

674

HR 1.2 (0.95 to 1.5)

Pooled

Prior nephrectomy

952

HR 1.2 (1.0 to 1.43), I2 = 0%

Hudes 2007

No prior nephrectomy

138

HR 1.7 (1.1 to 2.5)

Motzer 2007

No prior nephrectomy

76

HR 1.23 (0.8 to 2.1)

Pooled

No prior nephrectomy

214

HR 1.48 (1.1 to 2.0), I2 = 1%

Hudes 2007

KPS ≤ 70

340

HR 1.39 (1.11 to 1.75)

Hudes 2007

KPS > 70

75

HR 0.93 (0.53 to 1.67)

Motzer 2007

With poor risk

48

HR 1.15 (0.83 to 2.78)

Motzer 2007

Intermediate risk

421

HR 1.27 (1.00 to 1.62)

Motzer 2007

ECOG Performance Status 0

460

HR 1.1 (0.87 to 1.5)

Motzer 2007

ECOG Performance Status 1

290

HR 1.4 (1.05 to 1.7)

3 (IFN‐α alone vs IFN‐α + bevacizumab)

Escudier 2007

Favourable risk

180

HR 1.09 (0.73 to 1.61), P = 0.6798

Rini 2010

Favourable risk

192

HR 1.11 (0.8 to 1.56), P = 0.5189

Pooled

Favourable risk

372

HR 1.10 (0.85 to 1.43), I2 = 0%

Escudier 2007

Intermediate risk

392

HR 1.20 (0.95 to 1.54), P = 0.1230

Rini 2010

Intermediate risk

465

HR 1.15 (0.94 to 1.41), P = 0.1688

Pooled

Intermediate risk

857

HR 1.18 (1.01 to 1.37), I2 = 0%

Escudier 2007

Poor risk

59

HR 1.18 (0.68 to 2.04), P = 0.5594

Rini 2010

Poor risk

75

HR 1.33 (0.82 to 2.17), P = 0.2439

Pooled

Poor risk

124

HR 1.27 (0.88 to 1.82), I2 = 0%

Rini 2010

Prior nephrectomy

620

HR 1.10 (0.93 to 1.32), P = 0.2871

Rini 2010

No prior nephrectomy

112

HR 1.54 (1.02 to 2.27), P = 0.0381

5 (Vaccine treatment vs standard therapies)

Amato 2010

Favourable risk, treated with IL‐2 (SOC)

100

HR 0.54 (0.30 to 0.98), P = 0.046

Amato 2010

Favourable risk, treated with IFN‐α (SOC)

206

P > 0.05

Amato 2010

Good prognosis, treated with sunitinib (SOC)

119

P > 0.05

Amato 2010

Intermediate prognosis, treated with IL‐2 (SOC)

70

P > 0.05

Amato 2010

Intermediate prognosis, treated with IFN‐α (SOC)

169

P > 0.05

Amato 2010

Intermediate prognosis, treated with sunitinib (SOC)

65

P > 0.05

Rini 2015

Favourable risk (n = 92)

92

HR 0.82, P = 0.59

Rini 2015

Intermediate risk (n = 240)

240

HR 1.52, P < 0.05

6 (Targeted immunotherapy alone vs standard targeted therapies)

Motzer 2015a

Favourable risk group (MSKCC risk group)

293

HR 0.89 (0.59 to 1.32)

Motzer 2015a

Intermediate risk group (MSKCC risk group)

404

HR 0.76 (0.58 to 0.99)

Motzer 2015a

Poor risk group (MSKCC risk group)

124

HR 0.47 (0.30 to 0.73)

Motzer 2015a

1 previous antiangiogenic regimen

591

HR 0.71 (0.56 to 0.90)

Motzer 2015a

2 previous antiangiogenic regimens

230

HR 0.89 (0.61 to 1.29)

CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; HR: hazard ratio; IFN‐α: interferon‐α; IL: interleukin; KPS: Karnovsky Performance Score; MSKCC: Memorial Sloan‐Kettering Cancer Center; n: number of participants; SOC: standard of care.

Figures and Tables -
Table 2. Overall survival subgroups
Table 3. Quality of life

Comparison (group 1 vs group 0)

Study (reported in)

Measurement instrument

Group 1

Group 0

Favours

Difference (95% CI) or P values

1 (IFN‐α alone vs standard targeted therapies)

Motzer 2007 (reported in Cella 2008)

FACT‐G total score, mean postbaseline score over 17 weeks

76.8 (n = 357)

82.3 (n = 373)

Group 0

‐5.58 (‐7.25 to ‐3.91)

Motzer 2007 (reported in Cella 2008)

FKSI‐15, mean postbaseline score over 17 weeks

42.1 (n = 357)

45.3 (n = 373)

Group 0

‐3.27 (‐4.18 to ‐2.36)

Motzer 2007 (reported in Cella 2008)

FKSI‐DRS, mean postbaseline score over 17 weeks

27.4 (n = 357)

29.4 (n = 373)

Group 0

‐1.98 (‐2.51 to ‐1.46)

Hudes 2007, (reported in Yang 2010)

EQ‐5D Index, mean score on treatment

0.492 (n = 115)

0.590 (n = 157)

Group 0

‐0.099 (95% CI ‐0.162 to ‐0.036)

Motzer 2007 (reported in Cella 2008)

EQ‐5D Index, mean postbaseline score over 17 weeks

0.725 (n = 357)

0.762 (n = 373)

Group 0

‐0.0364 (‐0.0620 to ‐0.0109)

Pooled EQ‐5D

472

530

Group 0

‐0.06 (‐0.12 to 0), I2 = 69%

Hudes 2007, (reported in Yang 2010)

EQ‐VAS, mean score on treatment

58.83 (n = 115)

63.33 (n = 157)

Group 0

‐4.50 (‐8.184 to ‐0.819)

Motzer 2007, (reported in Cella 2008)

EQ‐VAS, mean postbaseline score over 17 weeks

68.7 (n = 357)

73.4 (n = 373)

Group 0

‐4.74 (‐6.87 to ‐2.60)

Pooled EQ‐VAS

472

530

Group 0

‐4.68 (‐6.53 to ‐2.83), I2 = 0%

6 (Targeted immunotherapy alone vs standard targeted therapies)

Motzer 2015a (reported in Cella 2016)

FKSI‐DRS, mean score at baseline

30.2 ± 4.4 (n = 362)

30.1 ± 4.8 (n = 344)

Difference in mean change 1.6 (1.4 to 1.9), P < 0.0001

FKSI‐DRS, mean change from baseline to week 28

0.4 ± 5 (n = 164)

‐1.2 ± 4 (n = 122)

Group 1

FKSI‐DRS, mean change from baseline to week 52

1.6 ± 4 (n = 97)

‐1.0 ± 6 (n = 63)

Group 1

FKSI‐DRS, mean change from baseline to week 104

3.5 ± 4.1 (n = 20)

0.2 ± 6 (n = 9)

Group 1

Clinically important improvement from baseline by ≥ 2 FKSI‐DRS points

200 (55%)/361

126 (37%)/343

Group 1

RR 1.51 (1.28 to 1.78); P < 0.0001

Time to clinically important improvement ≥ 2 FKSI‐DRS points

Median: 4.7 months (3.7 to 7.5)

Median not reached

Group 1

HR 1.66 (1.33 to 2.08); P < 0.0001

Clinically important improvement from baseline by ≥ 3 FKSI‐DRS points

148 (41%)/361

95 (28%)/343

Group 1

RR 1.48 (1.20 to 1.83); P = 0.0002

Time to clinically important improvement ≥ 3 FKSI‐DRS points

Median not estimable

Median not estimable

Group 1

HR 1.61 (1.24 to 2.09); P < 0.0003

EQ‐5D utility index, mean score at baseline

0.78 ± 0.24 (n = 362)

0.78 ± 0.21 (n = 344)

No significant differences in proportion of participants with clinical important improvements (P = 0.070) or time to improvement (P = 0.86).

EQ‐5D utility index, mean change from baseline to week 28

0.052 ± 0.22 (n = 164)

‐0.03 ± 0.2 (n = 122)

Group 1

EQ‐5D utility index, mean change from baseline to week 52

0.06 ± 0.1 (n = 98)

‐0.01 ± 0.2 (n = 63)

Group 1

EQ‐5D utility index, mean change from baseline to week 104

0.13 ± 0.7 (n = 20)

‐0.02 ± 0.15 (n = 9)

Group 1

EQ‐5D VAS, mean score at baseline

73.3 ± 18.5 (n = 362)

72.5 ± 18.7 (n = 344)

EQ‐5D VAS, mean change from baseline to week 28

5 ± 13 (n = 164)

‐3 ± 11 (n = 122)

Group 1

EQ‐5D VAS, mean change from baseline to week 52

7 ± 15 (n = 98)

‐2 ± 16 (n = 63)

Group 1

EQ‐5D VAS, mean change from baseline to week 104

9 ± 9 (n = 20)

1 ± 18 (n = 9)

Group 1

Clinically important improvement from baseline by ≥ 7 EQ‐5D VAS points

192 (53%)/360

134(39%)/343

RR 1.37 (1.16 to 1.61); P = 0.0001

Time to clinically important improvement

Median: 6.5 months (3.9 to 12.2)

Median: 23.1 months (15.4 to not estimated)

HR 1.37 (1.10 to 1.71)

CI: confidence interval; EQ‐5D Index: EuroQol 5‐Dimension (MID 0.06 to 0.08, Pickard 2007); EQ‐VAS: EuroQol Visual Analog Scale (MID 7, Pickard 2007); FACT‐G: Functional Assessment of Cancer Therapy ‐ General (MID 4 points for better rating and 8 points for worse rating, Ringash 2007); FKSI‐15: FACT‐Kidney Symptom Index (MID 3 points, Cella 1997); FKSI‐DRS: FACT‐Kidney Symptom Index Disease Related Symptoms (MID 2 points, Cella 1997); HR: hazard ratio; MID: minimal important difference; n: number of participants.

Figures and Tables -
Table 3. Quality of life
Comparison 1. Interferon‐α (IFN‐α) alone versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 1‐year mortality Show forest plot

2

1166

Risk Ratio (M‐H, Random, 95% CI)

1.30 [1.13, 1.51]

2 Overall survival Show forest plot

2

Hazard Ratio (Random, 95% CI)

1.28 [1.11, 1.49]

3 Quality of life Show forest plot

2

Mean Difference (Random, 95% CI)

Subtotals only

3.1 FACT‐G

1

730

Mean Difference (Random, 95% CI)

‐5.58 [‐7.25, ‐3.91]

3.2 FKSI‐15

1

730

Mean Difference (Random, 95% CI)

‐3.27 [‐4.18, ‐2.36]

3.3 FKSI‐DRS

1

730

Mean Difference (Random, 95% CI)

‐1.98 [‐2.51, ‐1.45]

3.4 EQ‐5D

2

1000

Mean Difference (Random, 95% CI)

‐0.06 [‐0.12, ‐0.00]

3.5 EQ‐VAS

2

1000

Mean Difference (Random, 95% CI)

‐4.68 [‐6.53, ‐2.83]

4 Adverse events (grade ≥ 3) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5 Progression‐free survival Show forest plot

2

Hazard Ratio (Random, 95% CI)

2.23 [1.79, 2.77]

6 Tumour remission Show forest plot

2

1007

Risk Ratio (M‐H, Random, 95% CI)

0.30 [0.12, 0.75]

Figures and Tables -
Comparison 1. Interferon‐α (IFN‐α) alone versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma
Comparison 2. Interferon‐α (IFN‐α) combined with targeted therapy versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 1‐year mortality Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2 Overall survival Show forest plot

1

Hazard Ratio (Random, 95% CI)

Subtotals only

3 Adverse events (grade ≥ 3) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4 Progression‐free survival Show forest plot

1

Hazard Ratio (Random, 95% CI)

Subtotals only

5 Tumour remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Figures and Tables -
Comparison 2. Interferon‐α (IFN‐α) combined with targeted therapy versus standard targeted therapy in first‐line therapy of metastatic renal cell carcinoma
Comparison 3. Interferon (IFN‐α) alone versus IFN‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 1‐year mortality Show forest plot

2

1381

Risk Ratio (M‐H, Random, 95% CI)

1.17 [1.00, 1.36]

2 Overall survival Show forest plot

2

Hazard Ratio (Random, 95% CI)

1.13 [1.00, 1.28]

3 Adverse events (grade ≥ 3) Show forest plot

2

1350

Risk Ratio (M‐H, Random, 95% CI)

0.77 [0.71, 0.84]

4 Progression‐free survival Show forest plot

2

Hazard Ratio (Random, 95% CI)

1.53 [1.36, 1.73]

5 Tumour remission Show forest plot

2

1205

Risk Ratio (M‐H, Random, 95% CI)

0.39 [0.31, 0.50]

Figures and Tables -
Comparison 3. Interferon (IFN‐α) alone versus IFN‐α plus bevacizumab in first‐line therapy of metastatic renal cell carcinoma
Comparison 4. Interferon‐α (IFN‐α) plus bevacizumab versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 1‐year mortality Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2 Adverse events (grade ≥ 3) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3 Progression‐free survival Show forest plot

1

Hazard Ratio (Random, 95% CI)

Subtotals only

4 Tumour remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Figures and Tables -
Comparison 4. Interferon‐α (IFN‐α) plus bevacizumab versus standard targeted therapies in first‐line therapy of metastatic renal cell carcinoma
Comparison 5. Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 1‐year mortality Show forest plot

2

1034

Risk Ratio (M‐H, Random, 95% CI)

1.10 [0.91, 1.32]

2 Overall survival Show forest plot

2

1071

Hazard Ratio (Fixed, 95% CI)

1.14 [0.96, 1.37]

3 Adverse events (grade ≥ 3) Show forest plot

2

1065

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.97, 1.39]

4 Progression‐free survival Show forest plot

1

339

Hazard Ratio (Random, 95% CI)

1.05 [0.87, 1.27]

5 Tumour remission Show forest plot

2

1071

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.76, 1.13]

Figures and Tables -
Comparison 5. Vaccine treatment versus standard therapies in first‐line therapy of metastatic renal cell carcinoma
Comparison 6. Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 1‐year mortality Show forest plot

1

821

Risk Ratio (M‐H, Random, 95% CI)

0.70 [0.56, 0.87]

2 Overall survival Show forest plot

1

Hazard Ratio (Random, 95% CI)

0.73 [0.60, 0.89]

3 Quality of life Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 Clinical important MID in FKSI‐DRS

1

704

Risk Ratio (M‐H, Random, 95% CI)

1.51 [1.28, 1.78]

3.2 Clinical important MID in EQ‐5D‐VAS

1

703

Risk Ratio (M‐H, Random, 95% CI)

1.37 [1.16, 1.61]

4 Adverse events (grade ≥ 3) Show forest plot

1

803

Risk Ratio (M‐H, Random, 95% CI)

0.51 [0.40, 0.65]

5 Progression‐free survival Show forest plot

1

Hazard Ratio (Random, 95% CI)

0.88 [0.75, 1.03]

6 Tumour remission Show forest plot

1

750

Risk Ratio (M‐H, Random, 95% CI)

4.39 [2.84, 6.80]

Figures and Tables -
Comparison 6. Targeted immunotherapy alone versus standard targeted therapies in previously treated patients with metastatic renal cell carcinoma