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Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page or to a histology- or biomarker-specific page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: This page contains trials that did not specify histology or allowed patients with multiple histologies. Trials limited to a specific histology including those that required a clear-cell component are on dedicated pages:

Histology-specific:
- Clear cell renal cell carcinoma
- Non-clear cell renal cell carcinoma
  - Papillary renal cell carcinoma
  - Sarcomatoid renal cell carcinoma
Biomarker-specific:
- RCC, VHL-associated

14 regimens on this page 22 variants on this page

Living Interactive Systematic Reviews

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ESMO

2021: Kanesveran et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with renal cell carcinoma PubMed
2021: Powles et al. ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma PubMed
2019: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2016: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2014: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2012: Escudier et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2010: Escudier & Kataja. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2009: Escudier & Kataja. Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed

ISRS

2024: Siva et al. Stereotactic body radiotherapy for primary renal cell carcinoma: a systematic review and practice guideline from the International Society of Stereotactic Radiosurgery (ISRS) PubMed

NCCN

NCCN Guidelines - Kidney Cancer
2022: Motzer et al. Kidney Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. PubMed
2017: Motzer et al. Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology PubMed
2015: Motzer et al. Kidney Cancer, Version 3.2015 PubMed
2014: Motzer et al. Kidney cancer, version 2.2014 PubMed
2011: Motzer et al. Kidney cancer. PubMed
2009: Motzer et al. NCCN clinical practice guidelines in oncology: kidney cancer. PubMed
2006: Motzer et al. Kidney cancer. Clinical practice guidelines in oncology. PubMed
2005: Motzer et al. Kidney cancer. Clinical practice guidelines. PubMed

SIOG

2018: Kanesvaran et al. Elderly patients with metastatic renal cell carcinoma: position paper from the International Society of Geriatric Oncology PubMed

SITC

2019: Rini et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC) PubMed

Risk Stratification Calculators

International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) calculator
- ref: Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK; External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013 Feb;14(2):141-8. Epub 2013 Jan 9. link to PMC article PubMed
Memorial Sloan Kettering Cancer Center (MSKCC) calculator
- ref: Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002 Jan 1;20(1):289-96. link to original article PubMed
Mortality and complication risk calculator for a patients with clinical T1 renal cortical mass up to 7 cm (Dr. Sarah P. Psutka)
- ref: Psutka SP et al., A clinical decision aid to support personalized treatment selection for patients with stage T1 renal masses: Results from a multi-institutional competing risks analysis including performance status and comorbidity. Working paper. link to news article
UCLA Integrated Staging System (UISS) for Renal Cell Carcinoma (RCC)
- ref: Zisman A, Pantuck AJ, Dorey F, Said JW, Shvarts O, Quintana D, Gitlitz BJ, deKernion JB, Figlin RA, Belldegrun AS. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol. 2001 Mar 15;19(6):1649-57. PubMed
Leibovich prognostic model
- ref: Leibovich BC, Lohse CM, Cheville JC, Zaid HB, Boorjian SA, Frank I, Thompson RH, Parker WP. Predicting Oncologic Outcomes in Renal Cell Carcinoma After Surgery. Eur Urol. 2018 May;73(5):772-780. Epub 2018 Feb 3. PubMed

Adjuvant therapy

Sunitinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Haas et al. 2016 (ECOG-ACRIN E2805)	2006-2010	Phase 3 (E-esc)	1. Placebo 2. Sorafenib	Did not meet primary endpoint of DFS

Preceding treatment

Surgery

Targeted therapy

Sunitinib (Sutent) 50 mg PO once per day on days 1 to 28

42-day cycle for up to 9 cycles (1 year)

References

ECOG-ACRIN E2805: Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16. Epub 2016 Mar 9. Erratum in: Lancet. 2016 May 14;387(10032):1998. link to original article link to PMC article PubMed NCT00326898

Metastatic disease, first-line

Atezolizumab & Bevacizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rini et al. 2019 (IMmotion151)	2015-05-20 to 2016-10-12	Phase 3 (E-esc)	Sunitinib	Seems to have superior PFS¹ (co-primary endpoint) Median PFS: 11.2 vs 7.7 mo (HR 0.74, 95% CI 0.57-0.96)

¹Reported efficacy is for the PD-L1-positive subgroup, which was the predefined co-primary endpoint.
Note: patients could have clear cell or sarcomatoid histology.

Immunotherapy

Atezolizumab (Tecentriq) 1200 mg IV once on day 1

Targeted therapy

Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

IMmotion151: Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. link to original article contains dosing details in abstract PubMed NCT02420821
1. Update: Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. link to original article [link to PMC article PubMed

Everolimus monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2014 (RECORD-3)	2009-2011	Randomized Phase 2 (E-switch-ic)	Sunitinib	Inconclusive whether non-inferior PFS (primary endpoint)

Targeted therapy

Everolimus (Afinitor) 10 mg PO once per day

Continued indefinitely

Subsequent treatment

RECORD-3, upon progression: Second-line Sunitinib

Dose and schedule modifications

Everolimus dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability

References

RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed NCT00903175

Gemcitabine & Sunitinib

Regimen

Study	Dates of enrollment	Evidence
Michaelson et al. 2015 (MGH 07-212)	2007-2013	Phase 2

Chemotherapy

Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

Targeted therapy

Sunitinib (Sutent) 37.5 mg PO once per day on days 1 to 14

21-day cycles

References

MGH 07-212: Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer. 2015 Oct 1;121(19):3435-43. Epub 2015 Jun 8. link to original article PubMed NCT00556049

High-dose Interleukin-2

HD IL-2: High-Dose InterLeukin-2

Example orders

Example orders for High-dose (HD) IL-2 in renal cancer

Regimen variant #1, 1.8 MU/kg/day, intermittent

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rosenberg et al. 1994	1985-1992	Non-randomized
Fyfe et al. 1995	NR	Phase 2 (RT)
McDermott et al. 2005	1997-2000	Phase 3 (C)	Subcutaneous IL-2 & Interferon	Might have superior PFS

Immunotherapy

IL-2 - Aldesleukin (Proleukin) 600,000 units/kg IV every 8 hours for up to 14 doses per week, on days 1 to 5, 15 to 19

Supportive therapy

Ciprofloxacin (Cipro) 250 mg PO twice per day on days 1 to 10, 15 to 24
All antihypertensive therapy discontinued at least 24 hours before each cycle
Acetaminophen (Tylenol) 650 mg PO every 4 hours
Indomethacin (Indocin) 25 mg PO every 6 hours
Ranitidine (Zantac) 150 mg PO or Famotidine (Pepcid) 20 mg PO every 12 hours
Hydroxyzine (Atarax) 25 to 50 mg PO every 6 hours or Diphenhydramine (Benadryl) 25 mg PO every (note: frequency was blank in reference) hours for pruritis
Meperidine (Demerol) 25 to 50 mg PO every 6 hours for chills and rigors
"An antidiarrheal agent, antiemetics, anxiolytics, diuretics, and vasopressors as needed"

28-day cycle for up to 3 cycles

Regimen variant #2, 2.16 MU/kg/day, intermittent, goal 10.8 MU

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yang et al. 1994	1991-1993	Phase 3 (C)	1. LD IL-2 (IV)	Seems to have superior ORR
Yang et al. 1994	1991-1993	Phase 3 (C)	2. LD IL-2 (SC)	Seems to have superior ORR

Note: reported efficacy is based on the 2003 update.

Immunotherapy

IL-2 - Aldesleukin (Proleukin) 720,000 units/kg IV every 8 hours for up to 15 doses
- Then after 7 to 10 days of rest, IL-2 - Aldesleukin (Proleukin) 720,000 units/kg IV every 8 hours for up to 15 doses is given again

8-week cycle for up to 2 cycles

Regimen variant #3, 5 MU/m²/day, CI

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Figlin et al. 1999	1994-1997	Phase 3 (C)	IL-2 & CD8+ TILs	Did not meet primary endpoint of ORR

Immunotherapy

IL-2 - Aldesleukin (Proleukin) 5,000,000 units/m²/day IV continuous infusion over 96 hours, started on days 1, 8, 15, 22 (total dose per cycle: 80 MU/m²)

8-week cycles

References

Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. link to original article PubMed
Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. link to original article PubMed
1. Update: Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. link to original article link to PMC article contains dosing details in manuscript PubMed
Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995 Mar;13(3):688-96. link to original article PubMed
Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P, Steinberg GD, Belldegrun AS. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. 1999 Aug;17(8):2521-9. link to original article contains dosing details in manuscript PubMed
McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005 Jan 1;23(1):133-41. link to original article contains dosing details in manuscript PubMed

Low-dose Interleukin-2

LD IL-2: Low-Dose InterLeukin-2

Regimen variant #1, Intravenous

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yang et al. 1994	1991-1993	Phase 3 (E-de-esc)	1. High-dose IL-2	Seems to have inferior ORR
Yang et al. 1994	1991-1993	Phase 3 (E-de-esc)	2. LD IL-2; SC	Not reported

Note: efficacy is based on the 2003 update.

Immunotherapy

IL-2 - Aldesleukin (Proleukin) as follows:
- Week 1: 72,000 units/kg IV every 8 hours for up to 15 doses
- Then after 7 to 10 days of rest: 72,000 units/kg IV every 8 hours for up to 15 doses is given again

8-week cycle for up to 2 cycles

Regimen variant #2, Subcutaneous

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Yang et al. 1994	1991-1993	Phase 3 (E-de-esc)	1. High-dose IL-2	Seems to have inferior ORR
Yang et al. 1994	1991-1993	Phase 3 (E-de-esc)	2. LD IL-2; IV	Not reported

Note: this arm was added to the trial after the interim results were announced in 1994.

Immunotherapy

IL-2 - Aldesleukin (Proleukin) as follows:
- Week 1: 250,000 units/kg SC once per day for 5 days
- Weeks 2 to 6: 125,000 units/kg SC once per day for 5 days per week

8-week cycle for up to 2 cycles

References

Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. link to original article PubMed
1. Update: Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. link to original article link to PMC article contains dosing details in manuscript PubMed

Interferon alfa-2a monotherapy

Regimen variant #1, 5 MU 5x per week

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sagaster et al. 1995	NR-1992	Phase 3 (C)	Cimetidine, Coumarin, IFN alfa-2a	Did not meet primary endpoint of ORR

Immunotherapy

Interferon alfa-2a (Roferon-A) 5,000,000 units SC once per day on days 1 to 5 (5 times per week)

7-day cycles

Regimen variant #2, 9 MU TIW

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gore et al. 2010 (MRC RE04/EORTC GU 30012)	2001-2006	Phase 3 (C)	5-FU, Interferon alfa-2a, IL-2	Did not meet primary endpoint of OS
Hawkins et al. 2016 (Active Biotech 06762004)	2007-2010	Phase 2/3 (C)	Naptumomab estafenatox + IFNα	Did not meet primary endpoint of OS

Immunotherapy

Interferon alfa-2a (Roferon-A) 9,000,000 units SC 3 times per week

Given for varying lengths of time; see individual trials

Dose and schedule modifications

Some protocols: Dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability

Regimen variant #3, 9 MU daily, with lead-in

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2000	1994-1996	Phase 3 (C)	IFN alfa & 13-CRA	Did not meet primary endpoint of ORR

Note: Interferon alfa-2a dose was increased only if the prior dose was tolerated.

Immunotherapy

Interferon alfa-2a (Roferon-A) as follows:
- Cycle 1: 3,000,000 units SC once per day on days 1 to 7
- Cycle 2: 6,000,000 units SC once per day on days 1 to 7
- Cycle 3 onwards: 9,000,000 units SC once per day on days 1 to 7

7-day cycles

Regimen variant #4, 10 MU TIW, with lead-in

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ritchie et al. 1999 (MRC RE01)	1992-1997	Phase 3 (E-switch-ooc)	MPA	Superior OS (primary endpoint) Median OS: 8.5 vs 6 mo (HR 0.72, 95% CI 0.55-0.94)

Immunotherapy

Interferon alfa-2a (Roferon-A) as follows:
- Cycle 1: 5,000,000 units SC once per day on days 1 & 3, then 10,000,000 units SC once on day 5
- Cycles 2 to 12: 10,000,000 units SC once per day on days 1, 3, 5 (3 times per week)

7-day cycle for 12 cycles

Regimen variant #5, 10 MU TIW

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gore et al. 2010 (MRC RE04/EORTC GU 30012)	2001-2006	Phase 3 (C)	5-FU, Interferon alfa-2a, IL-2	Did not meet primary endpoint of OS

Immunotherapy

Interferon alfa-2a (Roferon-A) 10,000,000 units SC once per day on days 1, 3, 5 (3 times per week)

7-day cycles

Regimen variant #6, 18 MU TIW, with lead-in

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fosså et al. 1992	1985-1986	Phase 3 (C)	IFN alfa-2a & Vinblastine	Did not meet efficacy endpoints
Hudes et al. 2007 (ARCC)	2003-2005	Phase 3 (C)	1. Interferon alfa-2a & Temsirolimus	Did not meet primary endpoint of OS
Hudes et al. 2007 (ARCC)	2003-2005	Phase 3 (C)	2. Temsirolimus	Inferior OS

Note: Interferon alfa-2a dose was increased only if the prior dose was tolerated.

Immunotherapy

Interferon alfa-2a (Roferon-A) as follows:
- Cycle 1: 3,000,000 units SC once per day on days 1, 3, 5
- Cycle 2: 9,000,000 units SC once per day on days 1, 3, 5
- Cycle 3 onwards: 18,000,000 units SC once per day on days 1, 3, 5

7-day cycles

Dose and schedule modifications

If higher doses cannot be tolerated, highest tolerable doses of 3,000,000, 4,500,500, or 6,000,000 units can be used

References

Fosså SD, Martinelli G, Otto U, Schneider G, Wander H, Oberling F, Bauer HW, Achtnicht U, Holdener EE. Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. Ann Oncol. 1992 Apr;3(4):301-5. link to original article PubMed
Sagaster P, Micksche M, Flamm J, Ludwig H. Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer. Ann Oncol. 1995 Dec;6(10):999-1003. link to original article contains dosing details in abstract PubMed
MRC RE01: Ritchie A, Griffiths G, Parmar M; Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet. 1999 Jan 2;353(9146):14-7. link to original article contains dosing details in abstract PubMed
Motzer RJ, Murphy BA, Bacik J, Schwartz LH, Nanus DM, Mariani T, Loehrer P, Wilding G, Fairclough DL, Cella D, Mazumdar M. Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol. 2000 Aug;18(16):2972-80. link to original article PubMed
ARCC: Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. link to original article contains dosing details in manuscript PubMed NCT00065468
MRC RE04/EORTC GU 30012: Gore ME, Griffin CL, Hancock B, Patel PM, Pyle L, Aitchison M, James N, Oliver RT, Mardiak J, Hussain T, Sylvester R, Parmar MK, Royston P, Mulders PF. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial. Lancet. 2010 Feb 20;375(9715):641-8. Epub 2010 Feb 10. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00053820
Active Biotech 06762004: Hawkins RE, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, Harza M, Polenkov S, Bondarenko I, Karlov P, Karyakin O, Khasanov R, Hedlund G, Forsberg G, Nordle Ö, Eisen T. A randomized phase II/III study of naptumomab estafenatox + IFNα versus IFNα in renal cell carcinoma: final analysis with baseline biomarker subgroup and trend analysis. Clin Cancer Res. 2016 Jul 1;22(13):3172-81. Epub 2016 Feb 5. link to original article contains dosing details in manuscript PubMed NCT00420888

Sorafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Stadler et al. 2010 (ARCCS)	2005-06 to 2006-07	Non-randomized
Retz et al. 2018 (SWITCH-II)	2012-06-14 to 2016-11-14	Phase 3 (C)	Pazopanib	Inconclusive whether non-inferior tPFS

Targeted therapy

Sorafenib (Nexavar) 400 mg PO twice per day

Continued indefinitely

Dose and schedule modifications

Sorafenib can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity

Subsequent treatment

SWITCH-II, upon progression: Pazopanib

References

ARCCS: Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. link to original article PubMed NCT00111020
SWITCH-II: Retz M, Bedke J, Bögemann M, Grimm MO, Zimmermann U, Müller L, Leiber C, Teber D, Wirth M, Bolenz C, van Alphen R, De Santis M, Beeker A, Lehmann J, Indorf M, Frank M, Bokemeyer C, Gschwend JE. SWITCH II: Phase III randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-pazopanib versus pazopanib-sorafenib in the treatment of advanced or metastatic renal cell carcinoma (AUO AN 33/11). Eur J Cancer. 2019 Jan;107:37-45. Epub 2018 Dec 7. link to original article contains dosing details in abstract PubMed NCT01613846

Sunitinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gore et al. 2009 (A618-1037)	2005-2007	Non-randomized
Motzer et al. 2014 (RECORD-3)	2009-2011	Randomized Phase 2 (E-switch-ic)	Everolimus	Inconclusive whether non-inferior PFS (primary endpoint)
Eichelberg et al. 2015 (SWITCH)	2009-2011	Phase 3 (C)	Sorafenib	Did not meet primary endpoint of PFS
Rini et al. 2019 (IMmotion151)	2015-05-20 to 2016-10-12	Phase 3 (C)	Atezolizumab & Bevacizumab	Seems to have inferior PFS

Targeted therapy

Sunitinib (Sutent) 50 mg PO once per day on days 1 to 28

42-day cycles

Subsequent treatment

SWITCH, upon progression: Second-line Sorafenib

Dose and schedule modifications

Per some references, dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability

References

A618-1037: Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. link to original article contains dosing details in manuscript PubMed NCT00130897
PISCES: Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol. 2014 May 10;32(14):1412-8. Epub 2014 Mar 31. link to original article PubMed NCT01064310
RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed NCT00903175
SWITCH: Eichelberg C, Vervenne WL, De Santis M, Fischer von Weikersthal L, Goebell PJ, Lerchenmüller C, Zimmermann U, Bos MM, Freier W, Schirrmacher-Memmel S, Staehler M, Pahernik S, Los M, Schenck M, Flörcken A, van Arkel C, Hauswald K, Indorf M, Gottstein D, Michel MS. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. Eur Urol. 2015 Nov;68(5):837-47. Epub 2015 May 4. link to original article contains dosing details in abstract PubMed NCT00732914
IMmotion151: Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. link to original article contains dosing details in abstract PubMed NCT02420821
1. Update: Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. link to original article [link to PMC article PubMed

Temsirolimus monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hudes et al. 2007 (ARCC)	2003-2005	Phase 3 (E-RT-switch-ooc)	1. Interferon alfa-2a	Superior OS (primary endpoint) Median OS: 10.9 vs 7.3 mo (HR 0.73, 95% CI 0.58-0.92)
Hudes et al. 2007 (ARCC)	2003-2005	Phase 3 (E-RT-switch-ooc)	2. Interferon alfa-2a & Temsirolimus	Not reported

Targeted therapy

Temsirolimus (Torisel) 25 mg IV over 30 minutes once on day 1

Supportive therapy

Diphenhydramine (Benadryl) (or similar H1 blocker) 25 to 50 mg IV once on day 1; 30 minutes prior to temsirolimus

7-day cycles

References

ARCC: Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. link to original article contains dosing details in manuscript PubMed NCT00065468

Metastatic disease, second-line

Cabozantinib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Pal et al. 2023 (CONTACT-03)	2020-07-28 to 2021-12-27	Phase 3 (C)	Cabozantinib & Atezolizumab	Did not meet co-primary endpoints of PFS/OS

Targeted therapy

Cabozantinib (Cabometyx) 60 mg PO once per day on days 1 to 28, taken at least 2 hours before or 1 hour after meals

28-day cycles

References

CONTACT-03: Pal SK, Albiges L, Tomczak P, Suárez C, Voss MH, de Velasco G, Chahoud J, Mochalova A, Procopio G, Mahammedi H, Zengerling F, Kim C, Osawa T, Angel M, Gupta S, Khan O, Bergthold G, Liu B, Kalaitzidou M, Huseni M, Scheffold C, Powles T, Choueiri TK. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023 Jul 15;402(10397):185-195. Epub 2023 Jun 5. link to original article contains dosing details in abstract PubMed NCT04338269

Everolimus monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2014 (RECORD-3)	2009-2011	Randomized Phase 2 (E-switch-ic)	Sunitinib	Inconclusive whether non-inferior PFS (primary endpoint)

Prior treatment criteria

RECORD-3: Sunitinib, with progression

Targeted therapy

Everolimus (Afinitor) 10 mg PO once per day

Continued indefinitely

Dose and schedule modifications

Everolimus dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability

References

RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed NCT00903175

Sorafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Stadler et al. 2010 (ARCCS)	2005-06 to 2006-07	Non-randomized expanded access study
Beck et al. 2011 (EU-ARCCS)	2005-2007	Non-randomized expanded access study
Hutson et al. 2013 (INTORSECT)	2007-2011	Phase 3 (C)	Temsirolimus	Did not meet primary endpoint of PFS² Median PFS: 3.9 vs 4.3 mo (HR 1.15, 95% CI 0.93-1.41)

¹Reported efficacy for TARGET is based on the 2009 update.
²While the primary endpoint (PFS) was not met in INTORSECT, the control arm actually had superior OS compared to the experimental arm.

Prior treatment criteria

INTORSECT: Sunitinib, with progression

Targeted therapy

Sorafenib (Nexavar) 400 mg PO twice per day

Continued indefinitely

Dose and schedule modifications

Sorafenib can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity

References

ARCCS: Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. link to original article PubMed NCT00111020
EU-ARCCS: Beck J, Procopio G, Bajetta E, Keilholz U, Negrier S, Szczylik C, Bokemeyer C, Bracarda S, Richel DJ, Staehler M, Strauss UP, Mersmann S, Burock K, Escudier B. Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. Ann Oncol. 2011 Aug;22(8):1812-23. Epub 2011 Feb 15. link to original article contains dosing details in manuscript PubMed
INTORSECT: Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, Motzer RJ. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Mar 10;32(8):760-7. Epub 2013 Dec 2. link to original article contains dosing details in abstract link to PMC article PubMed NCT00474786

Sunitinib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Motzer et al. 2005 (RTKC-0511-014)	2003	Phase 2 (RT)
Gore et al. 2009 (A618-1037)	2005-2007	Non-randomized
Motzer et al. 2014 (RECORD-3)	2009-2011	Randomized Phase 2 (E-switch-ic)	Everolimus	Inconclusive whether non-inferior PFS (primary endpoint)

Preceding treatment

RECORD-3: First-line Everolimus

Targeted therapy

Sunitinib (Sutent) 50 mg PO once per day on days 1 to 28

42-day cycles

Dose and schedule modifications

Dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability

References

RTKC-0511-014: Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006 Jan 1;24(1):16-24. Epub 2005 Dec 5. link to original article PubMed
A618-1037: Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. link to original article contains dosing details in manuscript PubMed NCT00130897
RECORD-3: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. link to original article link to PMC article PubMed NCT00903175

@@ Line 1: / Line 1: @@
-'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]].'''
+<span id="BackToTop"></span>
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
-Is there a regimen missing from this list?  Would you like to share a different dosage/schedule or an additional reference for a regimen?  Have you noticed an error?  Do you have an idea that will help the site grow to better meet your needs and the needs of many others?  You are [[How_to_contribute|invited to contribute to the site]].
+[[#top|Back to Top]]
+</div>
+{{#lst:Editorial board transclusions|rcc}}
+''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Renal_cell_carcinoma_-_historical|historical regimens page]] or to a histology- or biomarker-specific page. For placebo or observational studies in this condition, please visit [[Renal cell carcinoma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''<br>
+'''Note: This page contains trials that did not specify histology or allowed patients with multiple histologies. Trials limited to a specific histology including those that required a clear-cell component are on dedicated pages:'''
+*'''Histology-specific:'''
+**'''[[Clear cell renal cell carcinoma]]'''
+**'''[[Non-clear cell renal cell carcinoma]]'''
+***'''[[Papillary renal cell carcinoma]]'''
+***'''[[Sarcomatoid renal cell carcinoma]]'''
+*'''Biomarker-specific:'''
+**'''[[Renal_cell_carcinoma,_VHL-associated|RCC, VHL-associated]]'''
+{| class="wikitable" style="float:right; margin-right: 5px;"
+|-
+|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
+<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
+|}
 {{TOC limit|limit=3}}
+=Living Interactive Systematic Reviews=
+*[https://adjrcc.network-meta-analysis.com/ Adjuvant treatment options in renal cell carcinoma]
+*[https://rcc.network-meta-analysis.com/RCC.html Metastatic renal cell carcinoma (mRCC)]
-=Metastatic disease=
+=Guidelines=
-==Axitinib (Inlyta)==
+'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
-Level of Evidence:
+==[https://www.esmo.org/ ESMO]==
-<span
+*'''2021:''' Kanesveran et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8645910/ Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with renal cell carcinoma] [https://pubmed.ncbi.nlm.nih.gov/34864348/ PubMed]
-style="background:#00CD00;
+*'''2021:''' Powles et al. [https://doi.org/10.1016/j.annonc.2021.09.014 ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma] [https://pubmed.ncbi.nlm.nih.gov/34597799/ PubMed]
-padding:3px 6px 3px 6px;
+*'''2019:''' Escudier et al. [https://doi.org/10.1093/annonc/mdz056 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/30788497/ PubMed]
-border-color:black;
+**'''2016:''' Escudier et al. [https://doi.org/10.1093/annonc/mdw328 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/27664262/ PubMed]
-border-width:2px;
+**'''2014:''' Escudier et al. [https://doi.org/10.1093/annonc/mdu259 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/25210086/ PubMed]
-border-style:solid;">Phase III</span>
+**'''2012:''' Escudier et al. [https://doi.org/10.1093/annonc/mds227 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/22997456/ PubMed]
+**'''2010:''' Escudier & Kataja. [https://doi.org/10.1093/annonc/mdq206 Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555064/ PubMed]
+**'''2009:''' Escudier & Kataja. [https://doi.org/10.1093/annonc/mdp137 Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454473/ PubMed]
-===Regimen, Rini, et al. 2011 (AXIS) & Motzer, et al. 2013 (AXIS)===
+==ISRS==
-*[[Axitinib (Inlyta)]] 5 mg PO BID x at least 2 weeks
+*'''2024:''' Siva et al. [https://doi.org/10.1016/s1470-2045(23)00513-2 Stereotactic body radiotherapy for primary renal cell carcinoma: a systematic review and practice guideline from the International Society of Stereotactic Radiosurgery (ISRS)] [https://pubmed.ncbi.nlm.nih.gov/38181809/ PubMed]
-**Then if tolerated and BP not greater than 150/90, increased to [[Axitinib (Inlyta)]] 7 mg PO BID
-***Then if tolerated and BP not greater than 150/90, increased to [[Axitinib (Inlyta)]] 10 mg PO BID
-**Dose can be reduced to 2 to 3 mg PO BID if needed based on tolerability
-===References===
+==NCCN==
-# Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011 Dec 3;378(9807):1931-9. Epub 2011 Nov 4. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961613-9/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22056247 PubMed]
+*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440 NCCN Guidelines - Kidney Cancer]
-# '''Update:''' Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, Oudard S, Gore ME, Tarazi J, Hariharan S, Chen C, Rosbrook B, Kim S, Rini BI. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013 Apr 15. pii: S1470-2045(13)70093-7. doi: 10.1016/S1470-2045(13)70093-7. [Epub ahead of print] [http://www.sciencedirect.com/science/article/pii/S1470204513700937 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23598172 PubMed]
+*'''2022:''' Motzer et al. [https://doi.org/10.6004/Jnccn.2022.0001 Kidney Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/34991070/ PubMed]
+*'''2017:''' Motzer et al. [https://doi.org/10.6004/jnccn.2017.0100 Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology] [https://pubmed.ncbi.nlm.nih.gov/28596261/ PubMed]
+*'''2015:''' Motzer et al. [https://doi.org/10.6004/jnccn.2015.0022 Kidney Cancer, Version 3.2015] [https://pubmed.ncbi.nlm.nih.gov/25691606/ PubMed]
+*'''2014:''' Motzer et al. [https://doi.org/10.6004/jnccn.2014.0018 Kidney cancer, version 2.2014] [https://pubmed.ncbi.nlm.nih.gov/24586079/ PubMed]
+*'''2011:''' Motzer et al. [https://doi.org/10.6004/Jnccn.2011.0082 Kidney cancer.] [https://pubmed.ncbi.nlm.nih.gov/21917622/ PubMed]
+*'''2009:''' Motzer et al. [https://doi.org/10.6004/Jnccn.2009.0043 NCCN clinical practice guidelines in oncology: kidney cancer.] [https://pubmed.ncbi.nlm.nih.gov/19555584/ PubMed]
+*'''2006:''' Motzer et al. [https://doi.org/10.6004/Jnccn.2006.0089 Kidney cancer. Clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/17112454/ PubMed]
+*'''2005:''' Motzer et al. Kidney cancer. Clinical practice guidelines. [https://pubmed.ncbi.nlm.nih.gov/19813325/ PubMed]
-==Bevacizumab (Avastin)==
+==[https://siog.org/ SIOG]==
-===Regimen, Bukowski, et al. 2007===
+*'''2018:''' Kanesvaran et al. [https://doi.org/10.1016/S1470-2045(18)30125-6 Elderly patients with metastatic renal cell carcinoma: position paper from the International Society of Geriatric Oncology] [https://pubmed.ncbi.nlm.nih.gov/29893263/ PubMed]
-Level of Evidence:
+==SITC==
-<span
+*'''2019:''' Rini et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6924043/ The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC)] [https://pubmed.ncbi.nlm.nih.gov/31856918/ PubMed]
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Randomized Phase II, >20 per arm</span>
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV over 90 minutes (can subsequently be reduced to 60 and 30 minute infusions as tolerated) once every 2 weeks
+=Risk Stratification Calculators=
+*[https://www.mdcalc.com/heng-score-metastatic-renal-cell-carcinoma-rcc-prognosis International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) calculator]
-'''given for up to 104 weeks, until progression of disease, or unacceptable toxicity'''
+**ref: Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK; External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013 Feb;14(2):141-8. Epub 2013 Jan 9. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144042/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23312463/ PubMed]
+*[https://www.mdcalc.com/memorial-sloan-kettering-cancer-center-mskcc-motzer-score-metastatic-renal-cell-carcinoma-rcc Memorial Sloan Kettering Cancer Center (MSKCC) calculator]
+**ref: Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002 Jan 1;20(1):289-96. [https://doi.org/10.1200/JCO.2002.20.1.289?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed link to original article] [https://pubmed.ncbi.nlm.nih.gov/11773181/ PubMed]
+*[https://rgulati.shinyapps.io/rcc-risk-calculator/ Mortality and complication risk calculator for a patients with clinical T1 renal cortical mass up to 7 cm] (Dr. Sarah P. Psutka)
+**ref: Psutka SP et al., A clinical decision aid to support personalized treatment selection for patients with stage T1 renal masses: Results from a multi-institutional competing risks analysis including performance status and comorbidity. Working paper. [https://www.urotoday.com/conference-highlights/asco-gu-2020/asco-gu-2020-kidney-cancer/119296-asco-gu-2020-a-novel-clinical-decision-aid-to-support-personalized-treatment-selection-for-patients-with-ct1-renal-cortical-masses-results-from-a-multi-institutional-competing-risks-analysis-including-performance-status-and-comorbidity.html link to news article]
+*[https://www.mdcalc.com/ucla-integrated-staging-system-uiss-renal-cell-carcinoma-rcc UCLA Integrated Staging System (UISS) for Renal Cell Carcinoma (RCC)]
+**ref: Zisman A, Pantuck AJ, Dorey F, Said JW, Shvarts O, Quintana D, Gitlitz BJ, deKernion JB, Figlin RA, Belldegrun AS. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol. 2001 Mar 15;19(6):1649-57. [https://pubmed.ncbi.nlm.nih.gov/11250993/ PubMed]
+*Leibovich prognostic model
+**ref: Leibovich BC, Lohse CM, Cheville JC, Zaid HB, Boorjian SA, Frank I, Thompson RH, Parker WP. Predicting Oncologic Outcomes in Renal Cell Carcinoma After Surgery. Eur Urol. 2018 May;73(5):772-780. Epub 2018 Feb 3. [https://pubmed.ncbi.nlm.nih.gov/29398265/ PubMed]
+=Adjuvant therapy=
+==Sunitinib monotherapy {{#subobject:cf6852|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:3c0a01|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ Haas et al. 2016 (ECOG-ACRIN E2805)]
+|2006-2010
+| style="background-color:#1a9851" |Phase 3 (E-esc)
+|1. [[Renal_cell_carcinoma_-_null_regimens#Placebo|Placebo]]<br>2. [[#Sorafenib_monotherapy_999|Sorafenib]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*[[Surgery#Renal_cell_carcinoma_surgery|Surgery]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28
+'''42-day cycle for up to 9 cycles (1 year)'''
+</div></div>
 ===References===
-# Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S, Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA, McDermott D. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007 Oct 10;25(29):4536-41. Epub 2007 Sep 17. [http://jco.ascopubs.org/content/25/29/4536.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17876014 PubMed]
+#'''ECOG-ACRIN E2805:''' Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16. Epub 2016 Mar 9. Erratum in: Lancet. 2016 May 14;387(10032):1998. [https://doi.org/10.1016/S0140-6736(16)00559-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878938/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26969090/ PubMed] [https://clinicaltrials.gov/study/NCT00326898 NCT00326898]
+=Metastatic disease, first-line=
-==Bevacizumab & Erlotinib==
+==Atezolizumab & Bevacizumab {{#subobject:af0d04|Regimen=1}}==
-===Regimen, Bukowski, et al. 2007===
+<div class="toccolours" style="background-color:#eeeeee">
-Level of Evidence:
+===Regimen {{#subobject:34c462|Variant=1}}===
-<span
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-style="background:#00CD00;
+! style="width: 20%" |Study
-padding:3px 6px 3px 6px;
+! style="width: 20%" |Dates of enrollment
-border-color:black;
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-border-width:2px;
+! style="width: 20%" |Comparator
-border-style:solid;">Randomized Phase II, >20 per arm</span>
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV over 90 minutes (can subsequently be reduced to 60 and 30 minute infusions as tolerated) once every 2 weeks
+|[https://doi.org/10.1016/S0140-6736(19)30723-8 Rini et al. 2019 (IMmotion151)]
-*[[Erlotinib (Tarceva)]] 150 mg PO once per day
+|2015-05-20 to 2016-10-12
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-'''given for up to 104 weeks, until progression of disease, or unacceptable toxicity'''
+|[[#Sunitinib_monotherapy_2|Sunitinib]]
+| style="background-color:#91cf60" |Seems to have superior PFS<sup>1</sup> (co-primary endpoint)<br>Median PFS: 11.2 vs 7.7 mo<br>(HR 0.74, 95% CI 0.57-0.96)
-===References===
+|-
-# Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S, Vaishampayan U, Drabkin HA, Dutcher J, Ryba S, Xia Q, Scappaticci FA, McDermott D. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007 Oct 10;25(29):4536-41. Epub 2007 Sep 17. [http://jco.ascopubs.org/content/25/29/4536.full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17876014 PubMed]
+|}
+''<sup>1</sup>Reported efficacy is for the PD-L1-positive subgroup, which was the predefined co-primary endpoint.''<br>
-==Bevacizumab & Interferon alfa-2a==
+''Note: patients could have clear cell or sarcomatoid histology.''
-===Regimen, Escudier, et al. 2007 (AVOREN)===
+<div class="toccolours" style="background-color:#b3e2cd">
-Level of Evidence:
+====Immunotherapy====
-<span
+*[[Atezolizumab (Tecentriq)]] 1200 mg IV once on day 1
-style="background:#00CD00;
+====Targeted therapy====
-padding:3px 6px 3px 6px;
+*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
-border-color:black;
+'''21-day cycles'''
-border-width:2px;
+</div></div>
-border-style:solid;">Phase III</span>
+===References ===
+#'''IMmotion151:''' Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. [https://doi.org/10.1016/S0140-6736(19)30723-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31079938/ PubMed] [https://clinicaltrials.gov/study/NCT02420821 NCT02420821]
-*[[Bevacizumab (Avastin)]] 10 mg/kg IV once every 2 weeks
+##'''Update:''' Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. [https://doi.org/10.1001/jamaoncol.2021.5981 link to original article] [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855230/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34940781/ PubMed]
-*[[Interferon alfa-2a (Roferon-A)]] 9 million units SC 3 times per week
-**Dose can be reduced to 3 or 6 million units SC 3 times per week based on tolerability
-'''Interferon alfa-2a given for up to 52 weeks, until progression of disease, or unacceptable toxicity; bevacizumab given until progression of disease or unacceptable toxicity'''
-===References===
-# Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. [http://www.ncbi.nlm.nih.gov/pubmed/18156031 PubMed]
-# Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. doi: 10.1200/JCO.2008.16.9847. Epub 2008 Oct 20. [http://jco.ascopubs.org/content/26/33/5422.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18936475 PubMed]
-# '''Update:''' Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. [http://jco.ascopubs.org/content/28/13/2144.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20368553 PubMed]
-# '''Update:''' Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010 May 1;28(13):2137-43. doi: 10.1200/JCO.2009.26.5561. Epub 2010 Apr 5. [http://jco.ascopubs.org/content/28/13/2137.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/20368558 PubMed]
-==Erlotinib (Tarceva)==
-===Regimen, Gordon, et al. 2009 (SWOG S0317)===
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-*[[Erlotinib (Tarceva)]] 150 mg PO once per day, given 1 hour before or 2 hours after meals
-'''given until progression of disease or unacceptable toxicity'''
-===References===
-# Gordon MS, Hussey M, Nagle RB, Lara PN Jr, Mack PC, Dutcher J, Samlowski W, Clark JI, Quinn DI, Pan CX, Crawford D. Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol. 2009 Dec 1;27(34):5788-93. Epub 2009 Nov 2. [http://jco.ascopubs.org/content/27/34/5788.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19884559 PubMed]
-==Everolimus (Afinitor)==
-===Regimen, Motzer, et al. 2008 (RECORD-1)===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
+==Everolimus monotherapy {{#subobject:b3af63|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:474ade|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
+|2009-2011
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
+|[[#Sunitinib_monotherapy_2|Sunitinib]]
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
 *[[Everolimus (Afinitor)]] 10 mg PO once per day
-**Dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability
+'''Continued indefinitely'''
+</div>
-===References===
+<div class="toccolours" style="background-color:#cbd5e7">
-# Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2961039-9/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18653228 PubMed]
+====Subsequent treatment====
-# '''Update:''' Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A; RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer. 2010 Sep 15;116(18):4256-65. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.25219/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20549832 PubMed]
+*RECORD-3, upon progression: Second-line [[#Sunitinib_monotherapy_3|Sunitinib]]
+</div>
-==Gemcitabine & Doxorubicin==
+<div class="toccolours" style="background-color:#fff2ae">
-===Regimen, Roubaud, et al. 2011 & Haas, et al. 2012 (ECOG 8802)===
+====Dose and schedule modifications====
-Level of Evidence:
+*Everolimus dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability
-<span
+</div></div>
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-*[[Gemcitabine (Gemzar)]] 1500 mg/m2 IV over 30 minutes once on day 1
-*[[Doxorubicin (Adriamycin)]] 50 mg/m2 IV push once on day 1
-'''14-day cycles, given until cumulative Doxorubicin (Adriamycin) dose of 300 to 450 mg/m2 (depending on cardiac function), progression of disease, or unacceptable toxicity'''
-Supportive medications:
-*One of the following:
-**[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day on starting on day 2 or 3, given until day 10
-**[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2
 ===References===
-# Roubaud G, Gross-Goupil M, Wallerand H, de Clermont H, Dilhuydy MS, Ravaud A. Combination of gemcitabine and doxorubicin in rapidly progressive metastatic renal cell carcinoma and/or sarcomatoid renal cell carcinoma. Oncology. 2011;80(3-4):214-8. Epub 2011 Jul 1. [http://content.karger.com/produktedb/produkte.asp?DOI=10.1159/000329078 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21720184 PubMed]
+#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25049330/ PubMed] [https://clinicaltrials.gov/study/NCT00903175 NCT00903175]
-# Haas NB, Lin X, Manola J, Pins M, Liu G, McDermott D, Nanus D, Heath E, Wilding G, Dutcher J. A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802. Med Oncol. 2012 Jun;29(2):761-7. Epub 2011 Feb 6. [http://www.springerlink.com/content/dnk52234n2567m5h/?MUD=MP link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21298497 PubMed]
-==Gemcitabine & Sunitinib==
-===Regimen, Pandya, et al. 2011===
-Level of Evidence:
-<span
-style="background:#ff0000;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Retrospective</span>
-*[[Gemcitabine (Gemzar)]] 750 mg/m2 IV over 90 minutes once per day on days 1 & 8
-*[[Sunitinib (Sutent)]] 37.5 mg PO once per day on days 2 to 15
+==Gemcitabine & Sunitinib {{#subobject:ec76af|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:py1|Variant=1}}===
+{| class="wikitable" style="width: 60%; text-align:center;"
+! style="width: 33%" |Study
+! style="width: 33%" |Dates of enrollment
+! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
+|-
+|[https://doi.org/10.1002/cncr.29503 Michaelson et al. 2015 (MGH 07-212)]
+|2007-2013
+| style="background-color:#91cf61" |Phase 2
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Chemotherapy====
+*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
+====Targeted therapy====
+*[[Sunitinib (Sutent)]] 37.5 mg PO once per day on days 1 to 14
 '''21-day cycles'''
+</div></div>
 ===References===
-# Pandya SS, Mier JW, McDermott DF, Cho DC. Addition of gemcitabine at the time of sunitinib resistance in metastatic renal cell cancer. BJU Int. 2011 Oct;108(8 Pt 2):E245-9. doi: 10.1111/j.1464-410X.2011.10096.x. Epub 2011 Feb 14. [http://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2011.10096.x/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21320274 PubMed]
+#'''MGH 07-212:''' Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer. 2015 Oct 1;121(19):3435-43. Epub 2015 Jun 8. [https://doi.org/10.1002/cncr.29503 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26058385/ PubMed] [https://clinicaltrials.gov/study/NCT00556049 NCT00556049]
+==High-dose Interleukin-2 {{#subobject:d95f4e|Regimen=1}}==
-==High-dose (HD) IL-2==
+HD IL-2: '''<u>H</u>'''igh-'''<u>D</u>'''ose '''<u>I</u>'''nter'''<u>L</u>'''eukin-'''<u>2</u>'''
 ===Example orders===
 *[[Example orders for High-dose (HD) IL-2 in renal cancer]]
+<div class="toccolours" style="background-color:#eeeeee">
-===Regimen #1, McDermott, et al. 2005===
+===Regimen variant #1, 1.8 MU/kg/day, intermittent {{#subobject:ca472e|Variant=1}}===
-Level of Evidence:
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-<span
+! style="width: 20%" |Study
-style="background:#00CD00;
+! style="width: 20%" |Dates of enrollment
-padding:3px 6px 3px 6px;
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-border-color:black;
+! style="width: 20%" |Comparator
-border-width:2px;
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-border-style:solid;">Phase III</span>
+|-
+|[https://doi.org/10.1001/jama.1994.03510360033032 Rosenberg et al. 1994]
-*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 units/kg IV every 8 hours x up to 14 doses per week, on days 1 to 5, 15 to 19
+|1985-1992
+| style="background-color:#91cf61" |Non-randomized
-'''28-day cycles x up to 3 cycles'''
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
-Supportive medications:
+|-
-*Ciprofloxacin (Cipro) 250 mg PO BID on days 1 to 10, 15 to 24
+|[https://doi.org/10.1200/JCO.1995.13.3.688 Fyfe et al. 1995]
+|NR
+| style="background-color:#91cf61" |Phase 2 (RT)
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://doi.org/10.1200/jco.2005.03.206 McDermott et al. 2005]
+| 1997-2000
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Interferon_alfa-2a_.26_Interleukin-2_999|Subcutaneous IL-2 & Interferon]]
+| style="background-color:#d9ef8b" |Might have superior PFS
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 600,000 units/kg IV every 8 hours for up to 14 doses per week, on days 1 to 5, 15 to 19
+====Supportive therapy====
+*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10, 15 to 24
 *All antihypertensive therapy discontinued at least 24 hours before each cycle
-*Acetaminophen (Tylenol) 650 mg PO every 4 hours
+*[[Acetaminophen (Tylenol)]] 650 mg PO every 4 hours
-*Indomethacin (Indocin) 25 mg PO every 6 hours
+*[[Indomethacin (Indocin)]] 25 mg PO every 6 hours
-*Ranitidine (Zantac) 150 mg PO or Famotidine (Pepcid) 20 mg PO every 12 hours
+*[[Ranitidine (Zantac)]] 150 mg PO or [[Famotidine (Pepcid)]] 20 mg PO every 12 hours
-*Hydroxyzine (Atarax) 25 to 50 mg PO every 6 hours or Diphenhydramine (Benadryl) 25 mg PO every (note: frequency was blank in reference) hours for pruritis
+*[[Hydroxyzine (Atarax)]] 25 to 50 mg PO every 6 hours or [[Diphenhydramine (Benadryl)]] 25 mg PO every (note: frequency was blank in reference) hours for pruritis
-*Meperidine (Demerol) 25 to 50 mg PO every 6 hours for chills and rigors
+*[[Meperidine (Demerol)]] 25 to 50 mg PO every 6 hours for chills and rigors
 *"An antidiarrheal agent, antiemetics, anxiolytics, diuretics, and vasopressors as needed"
+'''28-day cycle for up to 3 cycles'''
-===Regimen #2, Yang, et al. 2003===
+</div></div><br>
-Level of Evidence:
+<div class="toccolours" style="background-color:#eeeeee">
-<span
+===Regimen variant #2, 2.16 MU/kg/day, intermittent, goal 10.8 MU {{#subobject:9867a|Variant=1}}===
-style="background:#00CD00;
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-padding:3px 6px 3px 6px;
+! style="width: 20%" |Study
-border-color:black;
+! style="width: 20%" |Dates of enrollment
-border-width:2px;
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-border-style:solid;">Phase III</span>
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours x up to 15 doses
+|-
-**Then after 7 to 10 days of rest, [[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours x up to 15 doses is given again
+| rowspan="2" |[https://doi.org/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
+| rowspan="2" |1991-1993
-'''8-week cycles x up to 2 cycles'''
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#Low-dose_Interleukin-2|LD IL-2 (IV)]]
-===Regimen #3, Klapper, et al. 2008===
+| style="background-color:#91cf60" |Seems to have superior ORR
-Level of Evidence:
+|-
-<span
+|2. [[#Low-dose_Interleukin-2|LD IL-2 (SC)]]
-style="background:#ff0000;
+| style="background-color:#91cf60" |Seems to have superior ORR
-padding:3px 6px 3px 6px;
+|-
-border-color:black;
+|}
-border-width:2px;
+''Note: reported efficacy is based on the 2003 update.''
-border-style:solid;">Retrospective</span>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
-*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours x up to 12 doses (reduced from originally up to 15 doses due to few patients tolerating 15 doses)
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 15 doses
-**Then after 10 to 15 days of rest, [[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours x up to 12 doses is given again
+**Then after 7 to 10 days of rest, [[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 720,000 units/kg IV every 8 hours for up to 15 doses is given again
+'''8-week cycle for up to 2 cycles'''
-After this one course of treatments--defined by the paper as "two cycles"--patients with stable to improved disease would receive additional courses of treatments every 2 months (no maximum number of courses listed)
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-Supportive medications:
+===Regimen variant #3, 5 MU/m<sup>2</sup>/day, CI {{#subobject:bd04b6|Variant=1}}===
-*"Routine administration of antipyretics, anti-inflammatories, antiemetics, antidiarrheals, and H2 antagonists."
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/JCO.1999.17.8.2521 Figlin et al. 1999]
+|1994-1997
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Interleukin-2_.26_TILs_999|IL-2 & CD8+ TILs]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 5,000,000 units/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on days 1, 8, 15, 22 (total dose per cycle: 80 MU/m<sup>2</sup>)
+'''8-week cycles'''
+</div></div>
 ===References===
-# Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. [http://jco.ascopubs.org/content/21/16/3127.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12915604 PubMed]
+#Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994 Mar 23-30;271(12):907-13. [https://doi.org/10.1001/jama.1994.03510360033032 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8120958/ PubMed]
-# McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005 Jan 1;23(1):133-41. [http://jco.ascopubs.org/content/23/1/133.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15625368 PubMed]
+#Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. [https://doi.org/10.1200/JCO.1994.12.8.1572 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8040669/ PubMed]
-# Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, Sherry RM, Royal RE, Steinberg SM, Rosenberg S. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008 Jul 15;113(2):293-301. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.23552/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18457330 PubMed]
+##'''Update:''' Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. [https://doi.org/10.1200/jco.2003.02.122 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12915604/ PubMed]
+#Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995 Mar;13(3):688-96. [https://doi.org/10.1200/JCO.1995.13.3.688 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7884429/ PubMed]
-==Low-dose (LD) IL-2==
+#Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P, Steinberg GD, Belldegrun AS. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. 1999 Aug;17(8):2521-9. [https://doi.org/10.1200/JCO.1999.17.8.2521 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10561318/ PubMed]
-===Regimen, Yang, et al. 2003===
+#McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005 Jan 1;23(1):133-41. [https://doi.org/10.1200/jco.2005.03.206 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15625368/ PubMed]
-Level of Evidence:
+==Low-dose Interleukin-2 {{#subobject:a2e938|Regimen=1}}==
-<span
+LD IL-2: '''<u>L</u>'''ow-'''<u>D</u>'''ose '''<u>I</u>'''nter'''<u>L</u>'''eukin-'''<u>2</u>'''
-style="background:#00CD00;
+<div class="toccolours" style="background-color:#eeeeee">
-padding:3px 6px 3px 6px;
+===Regimen variant #1, Intravenous {{#subobject:445b6c|Variant=1}}===
-border-color:black;
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-border-width:2px;
+! style="width: 20%" |Study
-border-style:solid;">Phase III</span>
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 72,000 units/kg IV every 8 hours x up to 15 doses
+! style="width: 20%" | Comparator
-**Then after 7 to 10 days of rest, [[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 72,000 units/kg IV every 8 hours x up to 15 doses is given again
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
-'''8-week cycles x up to 2 cycles'''
+| rowspan="2" |[https://doi.org/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
+| rowspan="2" | 1991-1993
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-de-esc)
+|1. [[#High-dose_Interleukin-2|High-dose IL-2]]
+| style="background-color:#fc8d59" |Seems to have inferior ORR
+|-
+|2. [[#Low-dose_Interleukin-2|LD IL-2]]; SC
+| style="background-color:#d3d3d3" |Not reported
+|-
+|}
+''Note: efficacy is based on the 2003 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] as follows:
+**Week 1: 72,000 units/kg IV every 8 hours for up to 15 doses
+**Then after 7 to 10 days of rest: 72,000 units/kg IV every 8 hours for up to 15 doses is given again
+'''8-week cycle for up to 2 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #2, Subcutaneous {{#subobject:cbb5b2|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="2" |[https://doi.org/10.1200/JCO.1994.12.8.1572 Yang et al. 1994]
+| rowspan="2" |1991-1993
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-de-esc)
+|1. [[#High-dose_Interleukin-2|High-dose IL-2]]
+| style="background-color:#fc8d59" |Seems to have inferior ORR
+|-
+|2. [[#Low-dose_Interleukin-2|LD IL-2]]; IV
+| style="background-color:#d3d3d3" |Not reported
+|-
+|}
+''Note: this arm was added to the trial after the interim results were announced in 1994.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] as follows:
+**Week 1: 250,000 units/kg SC once per day for 5 days
+**Weeks 2 to 6: 125,000 units/kg SC once per day for 5 days per week
+'''8-week cycle for up to 2 cycles'''
+</div></div>
 ===References===
-# Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. [http://jco.ascopubs.org/content/21/16/3127.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12915604 PubMed]
+#Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI, Levin R, Guleria A, MacFarlane MP, White RL, Einhorn JH, Seipp CA, Rosenberg SA. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994 Aug;12(8):1572-6. [https://doi.org/10.1200/JCO.1994.12.8.1572 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8040669/ PubMed]
+##'''Update:''' Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. [https://doi.org/10.1200/jco.2003.02.122 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275327/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12915604/ PubMed]
+==Interferon alfa-2a monotherapy {{#subobject:8f04d6|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #1, 5 MU 5x per week {{#subobject:f49d4e|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" | Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1093/oxfordjournals.annonc.a059097 Sagaster et al. 1995]
+|NR-1992
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Cimetidine.2C_Coumarin.2C_Interferon_alfa-2a_999|Cimetidine, Coumarin, IFN alfa-2a]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Interferon alfa-2a (Roferon-A)]] 5,000,000 units SC once per day on days 1 to 5 (5 times per week)
+'''7-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-==Subcutaneous IL-2==
+===Regimen variant #2, 9 MU TIW {{#subobject:524ccc|Variant=1}}===
-===Regimen, Yang, et al. 2003===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-Level of Evidence:
+! style="width: 20%" |Study
-<span
+! style="width: 20%" |Dates of enrollment
-style="background:#00CD00;
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
-padding:3px 6px 3px 6px;
+! style="width: 20%" |Comparator
-border-color:black;
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-border-width:2px;
+|-
-border-style:solid;">Phase III</span>
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ Gore et al. 2010 (MRC RE04/EORTC GU 30012)]
+|2001-2006
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Fluorouracil.2C_Interferon_alfa-2a.2C_Interleukin-2_999|5-FU, Interferon alfa-2a, IL-2]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|[https://doi.org/10.1158/1078-0432.ccr-15-0580 Hawkins et al. 2016 (Active Biotech 06762004)]
+|2007-2010
+| style="background-color:#1a9851" |Phase 2/3 (C)
+|[[#Naptumomab estafenatox_.26_Interferon_alfa_999|Naptumomab estafenatox + IFNα]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Interferon alfa-2a (Roferon-A)]] 9,000,000 units SC 3 times per week
+'''Given for varying lengths of time; see individual trials'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*Some protocols: Dose can be reduced to 3,000,000 or 6,000,000 units SC 3 times per week based on tolerability
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-*[[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 250,000 units/kg SC once per day x 5 days on week 1
+===Regimen variant #3, 9 MU daily, with lead-in {{#subobject:5f04fc|Variant=1}}===
-**Then [[Aldesleukin (Proleukin)|IL-2 - Aldesleukin (Proleukin)]] 125,000 units/kg SC once per day x 5 days per week during weeks 2 to 6
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" | Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/JCO.2000.18.16.2972 Motzer et al. 2000]
+|1994-1996
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Interferon_alfa_.26_13-CRA_999|IFN alfa & 13-CRA]]
+| style="background-color:#ffffbf" | Did not meet primary endpoint of ORR
+|-
+|}
+''Note: Interferon alfa-2a dose was increased only if the prior dose was tolerated.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Interferon alfa-2a (Roferon-A)]] as follows:
+**Cycle 1: 3,000,000 units SC once per day on days 1 to 7
+**Cycle 2: 6,000,000 units SC once per day on days 1 to 7
+**Cycle 3 onwards: 9,000,000 units SC once per day on days 1 to 7
+'''7-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #4, 10 MU TIW, with lead-in {{#subobject:leadd5|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S0140-6736(98)03544-2 Ritchie et al. 1999 (MRC RE01)]
+|1992-1997
+| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
+|[[Renal_cell_carcinoma_-_historical#Medroxyprogesterone_acetate_monotherapy|MPA]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 8.5 vs 6 mo<br>(HR 0.72, 95% CI 0.55-0.94)
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Interferon alfa-2a (Roferon-A)]] as follows:
+**Cycle 1: 5,000,000 units SC once per day on days 1 & 3, then 10,000,000 units SC once on day 5
+**Cycles 2 to 12: 10,000,000 units SC once per day on days 1, 3, 5 (3 times per week)
+'''7-day cycle for 12 cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen variant #5, 10 MU TIW {{#subobject:800dd5|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ Gore et al. 2010 (MRC RE04/EORTC GU 30012)]
+|2001-2006
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Fluorouracil.2C_Interferon_alfa-2a.2C_Interleukin-2_999|5-FU, Interferon alfa-2a, IL-2]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Interferon alfa-2a (Roferon-A)]] 10,000,000 units SC once per day on days 1, 3, 5 (3 times per week)
+'''7-day cycles'''
+</div></div><br>
+<div class="toccolours" style="background-color:#eeeeee">
-'''8-week cycles x up to 2 cycles'''
+===Regimen variant #6, 18 MU TIW, with lead-in {{#subobject:b28245|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1093/oxfordjournals.annonc.a058185 Fosså et al. 1992]
+|1985-1986
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Interferon_alfa-2a_.26_Vinblastine_999|IFN alfa-2a & Vinblastine]]
+| style="background-color:#ffffbf" |Did not meet efficacy endpoints
+|-
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa066838 Hudes et al. 2007 (ARCC)]
+| rowspan="2" |2003-2005
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
+|1. [[#Interferon_alfa-2a_.26_Temsirolimus_999|Interferon alfa-2a & Temsirolimus]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+|-
+|2. [[#Temsirolimus_monotherapy|Temsirolimus]]
+| style="background-color:#d73027" |Inferior OS
+|-
+|}
+''Note: Interferon alfa-2a dose was increased only if the prior dose was tolerated.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Immunotherapy====
+*[[Interferon alfa-2a (Roferon-A)]] as follows:
+**Cycle 1: 3,000,000 units SC once per day on days 1, 3, 5
+**Cycle 2: 9,000,000 units SC once per day on days 1, 3, 5
+**Cycle 3 onwards: 18,000,000 units SC once per day on days 1, 3, 5
+'''7-day cycles'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*If higher doses cannot be tolerated, highest tolerable doses of 3,000,000, 4,500,500, or 6,000,000 units can be used
+</div></div>
+=== References===
+# Fosså SD, Martinelli G, Otto U, Schneider G, Wander H, Oberling F, Bauer HW, Achtnicht U, Holdener EE. Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. Ann Oncol. 1992 Apr;3(4):301-5. [https://doi.org/10.1093/oxfordjournals.annonc.a058185 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1390305/ PubMed]
+# Sagaster P, Micksche M, Flamm J, Ludwig H. Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer. Ann Oncol. 1995 Dec;6(10):999-1003. [https://doi.org/10.1093/oxfordjournals.annonc.a059097 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8750152/ PubMed]
+#'''MRC RE01:''' Ritchie A, Griffiths G, Parmar M; Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet. 1999 Jan 2;353(9146):14-7. [https://doi.org/10.1016/S0140-6736(98)03544-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10023944/ PubMed]
+#Motzer RJ, Murphy BA, Bacik J, Schwartz LH, Nanus DM, Mariani T, Loehrer P, Wilding G, Fairclough DL, Cella D, Mazumdar M. Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol. 2000 Aug;18(16):2972-80. [https://doi.org/10.1200/JCO.2000.18.16.2972 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10944130/ PubMed]
+#'''ARCC:''' Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. [https://doi.org/10.1056/NEJMoa066838 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17538086/ PubMed] [https://clinicaltrials.gov/study/NCT00065468 NCT00065468]
+#'''MRC RE04/EORTC GU 30012:''' Gore ME, Griffin CL, Hancock B, Patel PM, Pyle L, Aitchison M, James N, Oliver RT, Mardiak J, Hussain T, Sylvester R, Parmar MK, Royston P, Mulders PF. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial. Lancet. 2010 Feb 20;375(9715):641-8. Epub 2010 Feb 10. [https://doi.org/10.1016/S0140-6736(09)61921-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835851/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20153039/ PubMed] [https://clinicaltrials.gov/study/NCT00053820 NCT00053820]
+#'''Active Biotech 06762004:''' Hawkins RE, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, Harza M, Polenkov S, Bondarenko I, Karlov P, Karyakin O, Khasanov R, Hedlund G, Forsberg G, Nordle Ö, Eisen T. A randomized phase II/III study of naptumomab estafenatox + IFNα versus IFNα in renal cell carcinoma: final analysis with baseline biomarker subgroup and trend analysis. Clin Cancer Res. 2016 Jul 1;22(13):3172-81. Epub 2016 Feb 5. [https://doi.org/10.1158/1078-0432.ccr-15-0580 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26851187/ PubMed] [https://clinicaltrials.gov/study/NCT00420888 NCT00420888]
+==Sorafenib monotherapy {{#subobject:fe45b0|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:90ba4d|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1002/cncr.24864 Stadler et al. 2010 (ARCCS)]
+|2005-06 to 2006-07
+| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://doi.org/10.1016/j.ejca.2018.11.001 Retz et al. 2018 (SWITCH-II)]
+|2012-06-14 to 2016-11-14
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Pazopanib_monotherapy|Pazopanib]]
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior tPFS
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy ====
+*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
+'''Continued indefinitely'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*Sorafenib can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment ====
+*SWITCH-II, upon progression: [[#Pazopanib_monotherapy_2|Pazopanib]]
+</div></div>
 ===References===
-# Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003 Aug 15;21(16):3127-32. [http://jco.ascopubs.org/content/21/16/3127.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12915604 PubMed]
+#'''ARCCS:''' Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. [https://doi.org/10.1002/cncr.24864 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20082451/ PubMed] [https://clinicaltrials.gov/study/NCT00111020 NCT00111020]
+#'''SWITCH-II:''' Retz M, Bedke J, Bögemann M, Grimm MO, Zimmermann U, Müller L, Leiber C, Teber D, Wirth M, Bolenz C, van Alphen R, De Santis M, Beeker A, Lehmann J, Indorf M, Frank M, Bokemeyer C, Gschwend JE. SWITCH II: Phase III randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-pazopanib versus pazopanib-sorafenib in the treatment of advanced or metastatic renal cell carcinoma (AUO AN 33/11). Eur J Cancer. 2019 Jan;107:37-45. Epub 2018 Dec 7. [https://doi.org/10.1016/j.ejca.2018.11.001 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30529901/ PubMed] [https://clinicaltrials.gov/study/NCT01613846 NCT01613846]
-==Interferon alfa-2a (Roferon-A)==
-===Regimen #1, Motzer, et al. 2007===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[Interferon alfa-2a (Roferon-A)]] 3 million units SC 3 times per week on week 1
-**Then if tolerated, 6 million units SC 3 times per week on week 2
-***Then if tolerated, 9 million units SC 3 times per week on week 3 and beyond
-'''given until progression of disease or unacceptable toxicity'''
-===Regimen #2, Hudes, et al. 2007===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[Interferon alfa-2a (Roferon-A)]] 3 million units SC 3 times per week on week 1
-**Then if tolerated, 9 million units SC 3 times per week on week 2
-***Then if tolerated, 18 million units SC 3 times per week on week 3 and beyond
-**If higher doses cannot be tolerated, highest tolerable doses of 3, 4.5, or 6 million units can be used
-===Regimen #3, Escudier, et al. 2007 (AVOREN)===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[Interferon alfa-2a (Roferon-A)]] 9 million units SC 3 times per week
-**Dose can be reduced to 3 or 6 million units SC 3 times per week based on tolerability
-'''Interferon alfa-2a given for up to 52 weeks, until progression of disease, or unacceptable toxicity'''
+==Sunitinib monotherapy {{#subobject:b4a97a|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:92e618|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/S1470-2045%2809%2970162-7 Gore et al. 2009 (A618-1037)]
+|2005-2007
+| style="background-color:#91cf61" | Non-randomized
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
+|2009-2011
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
+|[[#Everolimus_monotherapy|Everolimus]]
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)
+|-
+|[https://doi.org/10.1016/j.eururo.2015.04.017 Eichelberg et al. 2015 (SWITCH)]
+|2009-2011
+| style="background-color:#1a9851" | Phase 3 (C)
+|[[#Sorafenib_monotherapy|Sorafenib]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
+|-
+|[https://doi.org/10.1016/S0140-6736(19)30723-8 Rini et al. 2019 (IMmotion151)]
+|2015-05-20 to 2016-10-12
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Atezolizumab_.26_Bevacizumab|Atezolizumab & Bevacizumab]]
+| style="background-color:#fc8d59" |Seems to have inferior PFS
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28
+'''42-day cycles'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*SWITCH, upon progression: Second-line [[#Sorafenib_monotherapy_2|Sorafenib]]
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*Per some references, dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability
+</div></div>
 ===References===
-# Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. [http://www.nejm.org/doi/full/10.1056/NEJMoa065044 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17215529 PubMed]
+#'''A618-1037:''' Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. [https://doi.org/10.1016/S1470-2045%2809%2970162-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19615940/ PubMed] [https://clinicaltrials.gov/study/NCT00130897 NCT00130897]
-# Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. [http://www.nejm.org/doi/full/10.1056/NEJMoa066838 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17538086 PubMed]
+#'''PISCES:''' Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol. 2014 May 10;32(14):1412-8. Epub 2014 Mar 31. [https://doi.org/10.1200/JCO.2013.50.8267 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24687826/ PubMed] [https://clinicaltrials.gov/study/NCT01064310 NCT01064310]
-# Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. [http://www.ncbi.nlm.nih.gov/pubmed/18156031 PubMed]
+#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25049330/ PubMed] [https://clinicaltrials.gov/study/NCT00903175 NCT00903175]
-# Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. doi: 10.1200/JCO.2008.16.9847. Epub 2008 Oct 20. [http://jco.ascopubs.org/content/26/33/5422.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18936475 PubMed]
+#'''SWITCH:''' Eichelberg C, Vervenne WL, De Santis M, Fischer von Weikersthal L, Goebell PJ, Lerchenmüller C, Zimmermann U, Bos MM, Freier W, Schirrmacher-Memmel S, Staehler M, Pahernik S, Los M, Schenck M, Flörcken A, van Arkel C, Hauswald K, Indorf M, Gottstein D, Michel MS. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. Eur Urol. 2015 Nov;68(5):837-47. Epub 2015 May 4. [https://doi.org/10.1016/j.eururo.2015.04.017 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25952317/ PubMed] [https://clinicaltrials.gov/study/NCT00732914 NCT00732914]
-# '''Update:''' Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. Epub 2009 Jun 1. [http://jco.ascopubs.org/content/27/22/3584.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19487381 PubMed] content property of [http://hemonc.org HemOnc.org]
+#'''IMmotion151:''' Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. Epub 2019 May 9. [https://doi.org/10.1016/S0140-6736(19)30723-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31079938/ PubMed] [https://clinicaltrials.gov/study/NCT02420821 NCT02420821]
-# '''Update:''' Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S, Sneller V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010 May 1;28(13):2144-50. Epub 2010 Apr 5. [http://jco.ascopubs.org/content/28/13/2144.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20368553 PubMed]
+##'''Update:''' Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2022 Feb 1;8(2):275-280. [https://doi.org/10.1001/jamaoncol.2021.5981 link to original article] [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8855230/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34940781/ PubMed]
-# '''Update:''' Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010 May 1;28(13):2137-43. doi: 10.1200/JCO.2009.26.5561. Epub 2010 Apr 5. [http://jco.ascopubs.org/content/28/13/2137.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/20368558 PubMed]
-==Pazopanib (Votrient)==
-===Regimen, Hutson, et al. 2010; Sternberg, et al. 2010 (VEG105192); Hainsworth, et al. 2013===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[Pazopanib (Votrient)]] 800 mg PO once per day, given 1 hour before or 2 hours after meals
-'''given until progression of disease, unacceptable toxicity, death, or withdrawal of consent'''
+==Temsirolimus monotherapy {{#subobject:8160ec|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+=== Regimen {{#subobject:f56815|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="2" |[https://doi.org/10.1056/NEJMoa066838 Hudes et al. 2007 (ARCC)]
+| rowspan="2" |2003-2005
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|1. [[#Interferon_alfa-2a_monotherapy|Interferon alfa-2a]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>Median OS: 10.9 vs 7.3 mo<br>(HR 0.73, 95% CI 0.58-0.92)
+|-
+|2. [[#Interferon_alfa-2a_.26_Temsirolimus_999|Interferon alfa-2a & Temsirolimus]]
+| style="background-color:#d3d3d3" |Not reported
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Temsirolimus (Torisel)]] 25 mg IV over 30 minutes once on day 1
+====Supportive therapy====
+*[[Diphenhydramine (Benadryl)]] (or similar H1 blocker) 25 to 50 mg IV once on day 1; 30 minutes prior to temsirolimus
+'''7-day cycles'''
+</div></div>
 ===References===
-# Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010 Jan 20;28(3):475-80. doi: 10.1200/JCO.2008.21.6994. Epub 2009 Dec 14. [http://jco.ascopubs.org/content/28/3/475.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20008644 PubMed]
+#'''ARCC:''' Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. [https://doi.org/10.1056/NEJMoa066838 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17538086/ PubMed] [https://clinicaltrials.gov/study/NCT00065468 NCT00065468]
-# Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. Epub 2010 Jan 25. [http://jco.ascopubs.org/content/28/6/1061.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20100962 PubMed]
-# '''Update:''' Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013 Apr;49(6):1287-96. doi: 10.1016/j.ejca.2012.12.010. Epub 2013 Jan 12. [http://www.sciencedirect.com/science/article/pii/S095980491200980X link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23321547 PubMed]
-# Hainsworth JD, Rubin MS, Arrowsmith ER, Khatcheressian J, Crane EJ, Franco LA. Pazopanib as Second-Line Treatment After Sunitinib or Bevacizumab in Patients With Advanced Renal Cell Carcinoma: A Sarah Cannon Oncology Research Consortium Phase II Trial. Clin Genitourin Cancer. 2013 May 9. pii: S1558-7673(13)00052-9. doi: 10.1016/j.clgc.2013.04.006. [Epub ahead of print] [http://www.sciencedirect.com/science/article/pii/S1558767313000529 link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23665131 PubMed]
-==Placebo==
-===Regimen===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-''No treatment. Used as a comparator arm and here for reference purposes only.''
+=Metastatic disease, second-line=
+==Cabozantinib monotherapy {{#subobject:pyr1|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:pyv1|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
+|-
+|}
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" | Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/s0140-6736(23)00922-4 Pal et al. 2023 (CONTACT-03)]
+|2020-07-28 to 2021-12-27
+| style="background-color:#1a9851" | Phase 3 (C)
+|[[#Cabozantinib_.26_Atezolizumab_999|Cabozantinib & Atezolizumab]]
+| style="background-color:#ffffbf" |Did not meet co-primary endpoints of PFS/OS
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Cabozantinib (Cometriq)|Cabozantinib (Cabometyx)]] 60 mg PO once per day on days 1 to 28, taken at least 2 hours before or 1 hour after meals
+'''28-day cycles'''
+</div></div>
 ===References===
-# Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. Erratum in: N Engl J Med. 2007 Jul 12;357(2):203. [http://www.nejm.org/doi/full/10.1056/NEJMoa060655 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17215530 PubMed]
+#'''CONTACT-03:''' Pal SK, Albiges L, Tomczak P, Suárez C, Voss MH, de Velasco G, Chahoud J, Mochalova A, Procopio G, Mahammedi H, Zengerling F, Kim C, Osawa T, Angel M, Gupta S, Khan O, Bergthold G, Liu B, Kalaitzidou M, Huseni M, Scheffold C, Powles T, Choueiri TK. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023 Jul 15;402(10397):185-195. Epub 2023 Jun 5. [https://doi.org/10.1016/s0140-6736(23)00922-4 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/37290461/ PubMed] [https://clinicaltrials.gov/study/NCT04338269 NCT04338269]
-# Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2961039-9/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18653228 PubMed]
-# Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. Epub 2010 Jan 25. [http://jco.ascopubs.org/content/28/6/1061.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20100962 PubMed]
-# '''Update:''' Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A; RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer. 2010 Sep 15;116(18):4256-65. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.25219/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20549832 PubMed]
-# '''Update:''' Hutson TE, Bellmunt J, Porta C, Szczylik C, Staehler M, Nadel A, Anderson S, Bukowski R, Eisen T, Escudier B; Sorafenib TARGET Clinical Trial Group. Long-term safety of sorafenib in advanced renal cell carcinoma: follow-up of patients from phase III TARGET. Eur J Cancer. 2010 Sep;46(13):2432-40. Epub 2010 Jul 23. [http://www.ejcancer.info/article/S0959-8049%2810%2900637-4/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20656473 PubMed]
-# '''Update:''' Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013 Apr;49(6):1287-96. doi: 10.1016/j.ejca.2012.12.010. Epub 2013 Jan 12. [http://www.sciencedirect.com/science/article/pii/S095980491200980X link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23321547 PubMed]
-==Regorafenib (Stivarga)==
-===Regimen, Eisen, et al. 2012===
-Level of Evidence:
-<span
-style="background:#EEEE00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase II</span>
-*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21, given while fasting or after a light meal
-'''28-day cycles, given until progression of disease or unacceptable toxicity'''
+==Everolimus monotherapy {{#subobject:893557|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+=== Regimen {{#subobject:9d436d|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
+|2009-2011
+| style="background-color:#1a9851" | Randomized Phase 2 (E-switch-ic)
+|[[#Sunitinib_monotherapy_3|Sunitinib]]
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)
+|-
+|}
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*RECORD-3: [[#Sunitinib_monotherapy_2|Sunitinib]], with progression
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Everolimus (Afinitor)]] 10 mg PO once per day
+'''Continued indefinitely'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*Everolimus dose can be reduced to 5 mg PO once per day or every other day if needed based on tolerability
+</div></div>
 ===References===
-# Eisen T, Joensuu H, Nathan PD, Harper PG, Wojtukiewicz MZ, Nicholson S, Bahl A, Tomczak P, Pyrhonen S, Fife K, Bono P, Boxall J, Wagner A, Jeffers M, Lin T, Quinn DI. Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol. 2012 Oct;13(10):1055-62. doi: 10.1016/S1470-2045(12)70364-9. Epub 2012 Sep 6. [http://www.sciencedirect.com/science/article/pii/S1470204512703649 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22959186 PubMed]
+#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25049330/ PubMed] [https://clinicaltrials.gov/study/NCT00903175 NCT00903175]
-==Sorafenib (Nexavar)==
-===Regimen===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[Sorafenib (Nexavar)]] 400 mg PO BID
-**Can be decreased to [[Sorafenib (Nexavar)]] 400 mg PO once per day or [[Sorafenib (Nexavar)]] 400 mg PO every other day if needed due to toxicity
+==Sorafenib monotherapy {{#subobject:6e18d8|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:a50d71|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" | Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1002/cncr.24864 Stadler et al. 2010 (ARCCS)]
+|2005-06 to 2006-07
+| style="background-color:#91cf61" |Non-randomized expanded access study
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://doi.org/10.1093/annonc/mdq651 Beck et al. 2011 (EU-ARCCS)]
+|2005-2007
+| style="background-color:#91cf61" |Non-randomized expanded access study
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569683/ Hutson et al. 2013 (INTORSECT)]
+|2007-2011
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Temsirolimus_monotherapy_999|Temsirolimus]]
+| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<sup>2</sup><br>Median PFS: 3.9 vs 4.3 mo<br>(HR 1.15, 95% CI 0.93-1.41)
+|-
+|}
+''<sup>1</sup>Reported efficacy for TARGET is based on the 2009 update.''<br>
+''<sup>2</sup>While the primary endpoint (PFS) was not met in INTORSECT, the control arm actually had superior OS compared to the experimental arm.''<br>
+<div class="toccolours" style="background-color:#fdcdac">
+====Prior treatment criteria====
+*INTORSECT: Sunitinib, with progression
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Sorafenib (Nexavar)]] 400 mg PO twice per day
+'''Continued indefinitely'''
+</div>
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*Sorafenib can be decreased to 400 mg PO once per day or 400 mg PO every other day if needed due to toxicity
+</div></div>
 ===References===
-# Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. Erratum in: N Engl J Med. 2007 Jul 12;357(2):203. [http://www.nejm.org/doi/full/10.1056/NEJMoa060655 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17215530 PubMed]
+#'''ARCCS:''' Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, Hainsworth JD, Henderson CA, George JR, Hajdenberg J, Kindwall-Keller TL, Ernstoff MS, Drabkin HA, Curti BD, Chu L, Ryan CW, Hotte SJ, Xia C, Cupit L, Bukowski RM; ARCCS Study Investigators. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010 Mar 1;116(5):1272-80. [https://doi.org/10.1002/cncr.24864 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20082451/ PubMed] [https://clinicaltrials.gov/study/NCT00111020 NCT00111020]
-# '''Update:''' Hutson TE, Bellmunt J, Porta C, Szczylik C, Staehler M, Nadel A, Anderson S, Bukowski R, Eisen T, Escudier B; Sorafenib TARGET Clinical Trial Group. Long-term safety of sorafenib in advanced renal cell carcinoma: follow-up of patients from phase III TARGET. Eur J Cancer. 2010 Sep;46(13):2432-40. Epub 2010 Jul 23. [http://www.ejcancer.info/article/S0959-8049%2810%2900637-4/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20656473 PubMed]
+#'''EU-ARCCS:''' Beck J, Procopio G, Bajetta E, Keilholz U, Negrier S, Szczylik C, Bokemeyer C, Bracarda S, Richel DJ, Staehler M, Strauss UP, Mersmann S, Burock K, Escudier B. Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. Ann Oncol. 2011 Aug;22(8):1812-23. Epub 2011 Feb 15. [https://doi.org/10.1093/annonc/mdq651 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21324953/ PubMed]
-# Beck J, Procopio G, Bajetta E, Keilholz U, Negrier S, Szczylik C, Bokemeyer C, Bracarda S, Richel DJ, Staehler M, Strauss UP, Mersmann S, Burock K, Escudier B. Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. Ann Oncol. 2011 Aug;22(8):1812-23. Epub 2011 Feb 15. [http://annonc.oxfordjournals.org/content/22/8/1812.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21324953 PubMed]
+#'''INTORSECT:''' Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, Motzer RJ. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Mar 10;32(8):760-7. Epub 2013 Dec 2. [https://doi.org/10.1200/JCO.2013.50.3961 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569683/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24297950/ PubMed] [https://clinicaltrials.gov/study/NCT00474786 NCT00474786]
-# Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011 Dec 3;378(9807):1931-9. Epub 2011 Nov 4. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2961613-9/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22056247 PubMed]
-==Sunitinib (Sutent)==
-===Regimen===
-Level of Evidence:
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
+==Sunitinib monotherapy {{#subobject:f929da|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:955949|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 20%" |Study
+! style="width: 20%" |Dates of enrollment
+! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 20%" |Comparator
+! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1200/JCO.2005.02.2574 Motzer et al. 2005 (RTKC-0511-014)]
+|2003
+| style="background-color:#91cf61" |Phase 2 (RT)
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://doi.org/10.1016/S1470-2045%2809%2970162-7 Gore et al. 2009 (A618-1037)]
+|2005-2007
+| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#d3d3d3" |
+| style="background-color:#d3d3d3" |
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ Motzer et al. 2014 (RECORD-3)]
+|2009-2011
+| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
+|[[#Everolimus_monotherapy|Everolimus]]
+| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)
+|-
+|}
+<div class="toccolours" style="background-color:#cbd5e8">
+====Preceding treatment====
+*RECORD-3: First-line [[#Everolimus_monotherapy|Everolimus]]
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
 *[[Sunitinib (Sutent)]] 50 mg PO once per day on days 1 to 28
-**Dose may be decreased to [[Sunitinib (Sutent)]] 37.5 mg or 25 mg PO once per day depending on tolerability
+'''42-day cycles'''
+</div>
-'''42-day cycles, given until progression of disease or unacceptable toxicity'''
+<div class="toccolours" style="background-color:#fff2ae">
+====Dose and schedule modifications====
+*Dose may be decreased to 37.5 mg or 25 mg PO once per day depending on tolerability
+</div></div>
 ===References===
-# Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. [http://www.nejm.org/doi/full/10.1056/NEJMoa065044 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17215529 PubMed]
+#'''RTKC-0511-014:''' Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006 Jan 1;24(1):16-24. Epub 2005 Dec 5. [https://doi.org/10.1200/JCO.2005.02.2574 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16330672/ PubMed]
-# Choueiri TK, Plantade A, Elson P, Negrier S, Ravaud A, Oudard S, Zhou M, Rini BI, Bukowski RM, Escudier B. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol. 2008 Jan 1;26(1):127-31. [http://jco.ascopubs.org/content/26/1/127.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18165647 PubMed]
+#'''A618-1037:''' Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. [https://doi.org/10.1016/S1470-2045%2809%2970162-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19615940/ PubMed] [https://clinicaltrials.gov/study/NCT00130897 NCT00130897]
-# '''Update:''' Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. Epub 2009 Jun 1. [http://jco.ascopubs.org/content/27/22/3584.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19487381 PubMed]
+#'''RECORD-3:''' Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. Epub 2014 Jul 21. [https://doi.org/10.1200/jco.2013.54.6911 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5569681/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25049330/ PubMed] [https://clinicaltrials.gov/study/NCT00903175 NCT00903175]
-# Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009 Aug;10(8):757-63. Epub 2009 Jul 15. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970162-7/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19615940 PubMed]
-==Temsirolimus (Torisel)==
+[[Category:Renal cell carcinoma regimens]]
-===Regimen, Hudes, et al. 2007===
+[[Category:Disease-specific pages]]
-Level of Evidence:
+[[Category:Genitourinary cancers]]
-<span
-style="background:#00CD00;
-padding:3px 6px 3px 6px;
-border-color:black;
-border-width:2px;
-border-style:solid;">Phase III</span>
-*[[Temsirolimus (Torisel)]] 25 mg IV over 30 minutes once every week
-Supportive medications:
-*Diphenhydramine (Benadryl) "or similar H1 blocker" 25 to 50 mg IV once 30 minutes prior to temsirolimus
-===References===
-# Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. [http://www.nejm.org/doi/full/10.1056/NEJMoa066838 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17538086 PubMed]

Difference between revisions of "Renal cell carcinoma"

Latest revision as of 17:31, 28 June 2024

Living Interactive Systematic Reviews

Guidelines

ESMO

ISRS

NCCN

SIOG

SITC

Risk Stratification Calculators

Adjuvant therapy

Sunitinib monotherapy

Regimen

Preceding treatment

Targeted therapy

References

Metastatic disease, first-line

Atezolizumab & Bevacizumab

Regimen

Immunotherapy

Targeted therapy

References

Everolimus monotherapy

Regimen

Targeted therapy

Subsequent treatment

Dose and schedule modifications

References

Gemcitabine & Sunitinib

Regimen

Chemotherapy

Targeted therapy

References

High-dose Interleukin-2

Example orders

Regimen variant #1, 1.8 MU/kg/day, intermittent

Immunotherapy

Supportive therapy

Regimen variant #2, 2.16 MU/kg/day, intermittent, goal 10.8 MU

Immunotherapy

Regimen variant #3, 5 MU/m2/day, CI

Immunotherapy

References

Low-dose Interleukin-2

Regimen variant #1, Intravenous

Immunotherapy

Regimen variant #2, Subcutaneous

Immunotherapy

References

Interferon alfa-2a monotherapy

Regimen variant #1, 5 MU 5x per week

Immunotherapy

Regimen variant #2, 9 MU TIW

Immunotherapy

Dose and schedule modifications

Regimen variant #3, 9 MU daily, with lead-in

Immunotherapy

Regimen variant #4, 10 MU TIW, with lead-in

Immunotherapy

Regimen variant #5, 10 MU TIW

Immunotherapy

Regimen variant #6, 18 MU TIW, with lead-in

Immunotherapy

Dose and schedule modifications

References

Sorafenib monotherapy

Regimen

Targeted therapy

Dose and schedule modifications

Subsequent treatment

References

Sunitinib monotherapy

Regimen

Targeted therapy

Subsequent treatment

Dose and schedule modifications

References

Temsirolimus monotherapy

Regimen

Targeted therapy

Regimen variant #3, 5 MU/m²/day, CI