Skip to main content
PMC home page
Medline Book to support NIHPA logoLink to Medline Book to support NIHPA
. 2024 Aug;28(45):1–171. doi: 10.3310/JWTR4127

Temporary treatment cessation compared with continuation of tyrosine kinase inhibitors for adults with renal cancer: the STAR non-inferiority RCT.

Fiona Collinson, Kara-Louise Royle, Jayne Swain, Christy Ralph, Anthony Maraveyas, Tim Eisen, Paul Nathan, Robert Jones, David Meads, Tze Min Wah, Adam Martin, Janine Bestall, Christian Kelly-Morland, Christopher Linsley, Jamie Oughton, Kevin Chan, Elisavet Theodoulou, Gustavo Arias-Pinilla, Amy Kwan, Luis Daverede, Catherine Handforth, Sebastian Trainor, Abdulazeez Salawu, Christopher McCabe, Vicky Goh, David Buckley, Jenny Hewison, Walter Gregory, Peter Selby, Julia Brown, Janet Brown; all the STAR investigators
PMCID: PMC11403377  PMID: 39250424

Abstract

BACKGROUND

There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy.

TRIAL DESIGN

A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma.

METHODS

Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals.

INTERVENTIONS

At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death.

OBJECTIVE

To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years.

CO-PRIMARY OUTCOMES

For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and -0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire.

RESULTS

Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat -0.05 (-0.15 to 0.05); per-protocol 0.04 (-0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ -0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years.

LIMITATIONS

The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison.

FUTURE WORK

Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma.

CONCLUSIONS

Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians' perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible.

TRIAL REGISTRATION

This trial is registered as ISRCTN06473203.

FUNDING

This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.

Plain language summary

Treatment breaks in cancer are of significant interest to patients and health professionals. Renal cell carcinoma is the most common type of kidney cancer. Sunitinib and pazopanib are both targeted treatments. They were commonly used to treat advanced kidney cancer but often cause side effects, sometimes requiring use of a reduced dose or even stopping treatment. The STAR trial was designed to see whether planned treatment breaks made patients with advanced kidney cancer being treated with sunitinib and pazopanib feel better, without substantially affecting how well the treatment worked. After 24 weeks of treatment, patients took sunitinib and pazopanib either as they normally would or in the alternative way with planned treatment breaks. Treating patients in this way was continued until drug-related side effects stopped treatment, patients’ disease worsened while taking treatment or the patient died. The trial compared how well the different treatment strategies worked in terms of how long patients lived and their quality of life over that time. This trial is the largest United Kingdom trial in advanced renal cell carcinoma. Patients took part from 60 United Kingdom centres between 2012 and 2017. It was funded by the National Institute for Health and Care Research Health Technology Assessment Programme and run by the Leeds Clinical Trials Research Unit. In total, 920 patients took part. Four hundred and sixty-one patients were allocated to continue treatment and 459 were allocated to start at least one treatment break. Treatment breaks lasted on average 87 days. The length of time patients lived in both arms of the trial appeared similar, but this cannot be concluded due to insufficient information. Being allocated to have treatment breaks rather than continuing treatment did not negatively impact a patient’s quality of life. Additionally, allocating patients to have treatment breaks was shown to have significant cost savings compared to just continuing treatment. Importantly planned treatment breaks were shown to be feasible.

Full text of this article can be found in Bookshelf.

References

  1. UK CR. Kidney Cancer Statistics. n.d. URL: www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/kidney-cancer#heading-Zero (accessed 23 March 2023).
  2. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with Nivolumab. JAMA Oncol 2019;5(10):1411–20. doi: 10.1001/jamaoncol.2019.2187. [DOI] [PMC free article] [PubMed]
  3. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. Lancet 1999;353(9146):14–7. [PubMed]
  4. Pyrhonen S, Salminen E, Ruutu M, Lehtonen T, Nurmi M, Tammela T, et al. Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 1999;17(9):2859–67. doi: 10.1200/JCO.1999.17.9.2859. [DOI] [PubMed]
  5. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356(2):115–24. doi: 10.1056/NEJMoa065044. [DOI] [PubMed]
  6. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27(22):3584–90. doi: 10.1200/JCO.2008.20.1293. [DOI] [PMC free article] [PubMed]
  7. Pytel D, Sliwinski T, Poplawski T, Ferriola D, Majsterek I. Tyrosine kinase blockers: new hope for successful cancer therapy. Anticancer Agents Med Chem 2009;9(1):66–76. doi: 10.2174/187152009787047752. [DOI] [PubMed]
  8. National Institute for Health and Care Excellence (NICE). Sunitinib for the First-line Treatment of Advanced and/or Metastatic Renal Cell Carcinoma. 2009. URL: www.nice.org.uk/guidance/TA169 (accessed 23 March 2023).
  9. Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol 2009;10(8):757–63. doi: 10.1016/S1470-2045(09)70162-7. [DOI] [PubMed]
  10. Shepard DR, Garcia JA. Toxicity associated with the long-term use of targeted therapies in patients with advanced renal cell carcinoma. Expert Rev Anticancer Ther 2009;9(6):795–805. doi: 10.1586/era.09.29. [DOI] [PubMed]
  11. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28(6):1061–8. doi: 10.1200/JCO.2009.23.9764. [DOI] [PubMed]
  12. Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369(8):722–31. doi: 10.1056/NEJMoa1303989. [DOI] [PubMed]
  13. Motzer RHT, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, et al.; Choueiri TK, editor. Randomized, Open-label, Phase III Trial of Pazopanib Versus Sunitinib in First-line Treatment of Patients with Metastatic Renal Cell Carcinoma (MRCC): Results of the COMPARZ Trial. Vienna: European Society for Medical Oncology; 2012.
  14. Bushmakin AGCJ, Korytowsky B, Sandin R, Matczak E, Cella D, et al., editors. Sunitinib dosing schedule and data collection time points: impact on quality of life outcomes in metastatic renal cell carcinoma. European Society for Medical Oncology. Vienna: Elsevier Inc.; 2012.
  15. Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, et al. 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;32(14):1412–8. doi: 10.1200/JCO.2013.50.8267. [DOI] [PubMed]
  16. National Institute for Health and Care Excellence (NICE). Tivozanib for Treating Advanced Renal Cell Carcinoma. 2018 URL: www.nice.org.uk/Guidance/TA512 (accessed 23 March 2023).
  17. National Institute for Health and Care Excellence (NICE). Cabozantinib for Untreated Advanced Renal Cell Carcinoma. 2018. URL: www.nice.org.uk/Guidance/TA542 (accessed 23 March 2023).
  18. Maughan TS, James RD, Kerr DJ, Ledermann JA, Seymour MT, Topham C, et al.; Medical Research Council Colorectal Cancer Group. Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial. Lancet 2003;361(9356):457–64. doi: 10.1016/s0140-6736(03)12461-0. [DOI] [PubMed]
  19. Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, et al.; MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol 2011;12(7):642–53. doi: 10.1016/S1470-2045(11)70102-4. [DOI] [PMC free article] [PubMed]
  20. Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer – a GERCOR study. J Clin Oncol 2006;24:394–400. doi: 10.1200/JCO.2005.03.0106. [DOI] [PubMed]
  21. de Gramont A, Buyse M, Abrahantes JC, Burzykowski T, Quinaux E, Cervantes A, et al. Reintroduction of oxaliplatin is associated with improved survival in advanced colorectal cancer. J Clin Oncol 2007;25(22):3224–9. doi: 10.1200/JCO.2006.10.4380. [DOI] [PubMed]
  22. Chibaudel B, Maindrault-Goebel F, Lledo G, Mineur L, Andre T, Bennamoun M, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol 2009;27(34):5727–33. doi: 10.1200/JCO.2009.23.4344. [DOI] [PubMed]
  23. Maughan T, Adams R, Wilson R, Seymour M, Meade A, Kaplan R. Chemotherapy-free intervals for patients with metastatic colorectal cancer remain an option. J Clin Oncol 2010;28(17):e275–6; author reply e277; author reply e7–8. doi: 10.1200/JCO.2009.27.8218. [DOI] [PubMed]
  24. Pereira AA, Rego JF, Munhoz RR, Hoff PM, Sasse AD, Riechelmann RP. The impact of complete chemotherapy stop on the overall survival of patients with advanced colorectal cancer in first-line setting: a meta-analysis of randomized trials. Acta Oncol 2015;54(10):1737–46. doi: 10.3109/0284186X.2015.1044022. [DOI] [PubMed]
  25. Berry SR, Cosby R, Asmis T, Chan K, Hammad N, Krzyzanowska MK; Cancer Care Ontario's Gastrointestinal Disease Site Group. Continuous versus intermittent chemotherapy strategies in metastatic colorectal cancer: a systematic review and meta-analysis. Ann Oncol 2015;26(3):477–85. doi: 10.1093/annonc/mdu272. [DOI] [PubMed]
  26. National Institute for Health and Care Excellence (NICE). COVID-19 Rapid Guideline: Delivery of Systemic Anticancer Treatments. 2020. URL: www.nice.org.uk/guidance/ng161/resources/covid19-rapid-guideline-delivery-of-systemic-anticancer-treatments-pdf-66141895710661 (accessed 23 March 2023). [PubMed]
  27. Blay JY, Le Cesne A, Ray-Coquard I, Bui B, Duffaud F, Delbaldo C, et al. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol 2007;25(9):1107–13. doi: 10.1200/JCO.2006.09.0183. [DOI] [PubMed]
  28. Zama IN, Hutson TE, Elson P, Cleary JM, Choueiri TK, Heng DY, et al. Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer 2010;116(23):5400–6. doi: 10.1002/cncr.25583. [DOI] [PubMed]
  29. Oudard S, Geoffrois L, Guillot A, Chevreau C, Deville JL, Falkowski S, et al. Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma-Results of the REchallenge with SUnitinib in MEtastatic RCC (RESUME) Study. Eur J Cancer 2016;62:28–35. doi: 10.1016/j.ejca.2016.04.003. [DOI] [PubMed]
  30. Kahl C, Hilgendorf I, Freund M, Casper J. Continuous therapy with sunitinib in patients with metastatic renal cell carcinoma. Onkologie 2008;31(8–9):485. doi: 10.1159/000142359. [DOI] [PubMed]
  31. Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24(16):2505–12. doi: 10.1200/JCO.2005.03.6723. [DOI] [PubMed]
  32. Ornstein MC, Wood LS, Elson P, Allman KD, Beach J, Martin A, et al. A Phase II Study of intermittent sunitinib in previously untreated patients with metastatic renal cell carcinoma. J Clin Oncol 2017;35(16):1764–9. doi: 10.1200/JCO.2016.71.1184. [DOI] [PubMed]
  33. Fogli S, Porta C, Del Re M, Crucitta S, Gianfilippo G, Danesi R, et al. Optimizing treatment of renal cell carcinoma with VEGFR-TKIs: a comparison of clinical pharmacology and drug-drug interactions of anti-angiogenic drugs. Cancer Treat Rev 2020;84:101966. doi: 10.1016/j.ctrv.2020.101966. [DOI] [PubMed]
  34. Atkins MB, Tannir NM. Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma. Cancer Treat Rev 2018;70:127–37. doi: 10.1016/j.ctrv.2018.07.009. [DOI] [PubMed]
  35. Deleuze A, Saout J, Dugay F, Peyronnet B, Mathieu R, Verhoest G, et al. Immunotherapy in renal cell carcinoma: the future is now. Int J Mol Sci 2020;21(7):2532. doi: 10.3390/ijms21072532. [DOI] [PMC free article] [PubMed]
  36. Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, et al.; CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378(14):1277–90. doi: 10.1056/NEJMoa1712126. [DOI] [PMC free article] [PubMed]
  37. Taguchi S, Buti S, Fukuhara H, Otsuka M, Bersanelli M, Morikawa T, et al. Benefit of adjuvant immunotherapy in renal cell carcinoma: a myth or a reality? PLOS ONE 2017;12(2):e0172341. doi: 10.1371/journal.pone.0172341. [DOI] [PMC free article] [PubMed]
  38. Gul A, Rini BI. Adjuvant therapy in renal cell carcinoma. Cancer 2019;125(17):2935–44. doi: 10.1002/cncr.32144. [DOI] [PubMed]
  39. Martini A, Fallara G, Pellegrino F, Cirulli GO, Larcher A, Necchi A, et al. Neoadjuvant and adjuvant immunotherapy in renal cell carcinoma. World J Urol 2021;39(5):1369–76. doi: 10.1007/s00345-020-03550-z. [DOI] [PubMed]
  40. MD+CALC. IMDC (International Metastatic RCC Database Consortium) Risk Score for RCC. 2021. URL: www.mdcalc.com/imdc-international-metastatic-rcc-database-consortium-risk-score-rcc (accessed 23 March 2023).
  41. Mekhail TM, Abou-Jawde RM, Boumerhi G, Malhi S, Wood L, Elson P, Bukowski R. Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol 2005;23(4):832–41. doi: 10.1200/JCO.2005.05.179. [DOI] [PubMed]
  42. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378:1931–9. doi: 10.1016/S0140-6736(11)61613-9. [DOI] [PubMed]
  43. Mehta A, Sonpavde G, Escudier B. Tivozanib for the treatment of renal cell carcinoma: results and implications of the TIVO-1 trial. Future Oncol 2014;10(11):1819–26. doi: 10.2217/fon.14.120. [DOI] [PubMed]
  44. National Institute for Health and Care Excellence (NICE). Cabozantinib for Previously Treated Advanced Renal Cell Carcinoma. 2017. URL: www.nice.org.uk/guidance/ta463 (accessed 26 September 2022).
  45. Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer 2018;94:115–25. doi: 10.1016/j.ejca.2018.02.012. [DOI] [PMC free article] [PubMed]
  46. Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372(7):621–30. doi: 10.1056/NEJMoa1406470. [DOI] [PubMed]
  47. Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015;16(15):1473–82. doi: 10.1016/S1470-2045(15)00290-9. [DOI] [PubMed]
  48. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al.; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373(19):1803–13. doi: 10.1056/NEJMoa1510665. [DOI] [PMC free article] [PubMed]
  49. Rassy E, Flippot R, Albiges L. Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma. Ther Adv Med Oncol 2020;12:1758835920907504. doi: 10.1177/1758835920907504. [DOI] [PMC free article] [PubMed]
  50. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al.; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380(12):1116–27. doi: 10.1056/NEJMoa1816714. [DOI] [PubMed]
  51. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380(12):1103–15. doi: 10.1056/NEJMoa1816047. [DOI] [PMC free article] [PubMed]
  52. Flippot R, Escudier B, Albiges L. Immune checkpoint inhibitors: toward new paradigms in renal cell carcinoma. Drugs 2018;78(14):1443–57. doi: 10.1007/s40265-018-0970-y. [DOI] [PubMed]
  53. Bedke J, Albiges L, Capitanio U, Giles RH, Hora M, Lam TB, et al. The 2021 Updated European association of urology guidelines on renal cell carcinoma: immune checkpoint inhibitor-based combination therapies for treatment-naive metastatic clear-cell renal cell carcinoma are standard of care. Eur Urol 2021;80(4):393–7. doi: 10.1016/j.eururo.2021.04.042. [DOI] [PubMed]
  54. Renfro LA, Grothey AM, Paul J, Floriani I, Bonnetain F, Niedzwiecki D, et al. Projecting event-based analysis dates in clinical trials: an illustration based on the international duration evaluation of adjuvant chemotherapy (IDEA) collaboration. Projecting analysis dates for the IDEA collaboration. Forum Clin Oncol 2014;5(2):1–7. doi: 10.2478/fco-2014-0006. [DOI] [PMC free article] [PubMed]
  55. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al.; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356(2):125–34. doi: 10.1056/NEJMoa060655. [DOI] [PubMed]
  56. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009;27(20):3312–8. doi: 10.1200/JCO.2008.19.5511. [DOI] [PubMed]
  57. Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27(8):1280–9. doi: 10.1200/JCO.2008.19.3342. [DOI] [PubMed]
  58. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 2008;26(33):5422–8. doi: 10.1200/JCO.2008.16.9847. [DOI] [PMC free article] [PubMed]
  59. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al.; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007;370(9605):2103–11. doi: 10.1016/S0140-6736(07)61904-7. [DOI] [PubMed]
  60. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349(5):427–34. doi: 10.1056/NEJMoa021491. [DOI] [PMC free article] [PubMed]
  61. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999;17(8):2530–40. doi: 10.1200/JCO.1999.17.8.2530. [DOI] [PubMed]
  62. Ltd NPU. Votrient 200 mg Film Coated Tablets – Summary of Product Characteristics. 2019. URL: www.medicines.org.uk/emc/product/7861/smpc (accessed 14 November 2019).
  63. EuroQol Research Foundation. EQ-5D-3L User Guide. 2018. URL: https://euroqol.org/publications/user-guides/ (accessed 23 March 2023).
  64. Allegra C, Blanke C, Buyse M, Goldberg R, Grothey A, Meropol NJ, et al. End points in advanced colon cancer clinical trials: a review and proposal. J Clin Oncol 2007;25(24):3572–5. doi: 10.1200/JCO.2007.12.1368. [DOI] [PubMed]
  65. Dolan P, Gudex C, Kind P, Williams A. A Social Tariff for EuroQol: Results from a UK General Population Survey. Discussion Paper Number 138. New York: Centre for Health Economics, University of York; 1995.
  66. Group F. FKSI-DRS Scoring Downloads. 2021 URL: www.facit.org/measures-scoring-downloads/fksi-drs-scoring-downloads (accessed 23 March 2023).
  67. Group F. FKSI-15 Scoring Downloads. 2021. URL: www.facit.org/measures-scoring-downloads/fksi-15-scoring-downloads (accessed 23 March 2023).
  68. Group F. Scoring of the FACIT Measures. 2021. URL: www.facit.org/scoring (accessed 23 March 2023).
  69. Group F. FACT-G Scoring Downloads. 2021. URL: www.facit.org/measures-scoring-downloads/fact-g-scoring-downloads (accessed 23 March 2023).
  70. Kessler DMA, editor. Introducing the FMM procedure for finite mixture models. SAS Global Forum 2012. 2012. URL: https://support.sas.com/resources/papers/proceedings12/328-2012.pdf (accessed 23 March 2023).
  71. Faria R, Gomes M, Epstein D, White IR. A guide to handling missing data in cost-effectiveness analysis conducted within randomised controlled trials. PharmacoEconomics 2014;32(12):1157–70. doi: 10.1007/s40273-014-0193-3. [DOI] [PMC free article] [PubMed]
  72. Simons CL, Rivero-Arias O, Yu LM, Simon J. Multiple imputation to deal with missing EQ-5D-3L data: should we impute individual domains or the actual index? Qual Life Res 2015;24(4):805–15. doi: 10.1007/s11136-014-0837-y. [DOI] [PubMed]
  73. White IR, Royston P, Wood AM. Multiple imputation using chained equations: issues and guidance for practice. Stat Med 2011;30(4):377–99. doi: 10.1002/sim.4067. [DOI] [PubMed]
  74. Morris TP, White IR, Royston P. Tuning multiple imputation by predictive mean matching and local residual draws. BMC Med Res Methodol 2014;14:75. doi: 10.1186/1471-2288-14-75. [DOI] [PMC free article] [PubMed]
  75. National Institute for Health and Care Excellence (NICE). Guide to the Methods of Technology Appraisal 2013. 2013. URL: www.nice.org.uk/process/pmg9/chapter/foreword (accessed 4 April 2013). [PubMed]
  76. National Institute for Health and Care Excellence (NICE). British National Formulary (BNF). 2020. URL: https://bnf.nice.org.uk/ (accessed 2 September 2021).
  77. Curtis L, Burns A. Unit Costs of Health and Social Care 2016. Canterbury, UK: Personal Social Services Research Unit, The University of Kent; 2016.
  78. Health Do. NHS Reference Costs 2015–2016. 2017. URL: www.gov.uk/government/publications/nhs-reference-costs-2015-to-2016 (accessed 15 December 2016).
  79. Care MCC. Understanding the Cost of End of Life Care in Different Settings. February 2012. URL: www.mariecurie.org.uk/globalassets/media/documents/commissioning-our-services/publications/understanding-cost-end-life-care-different-settingspdf (accessed 23 March 2023).
  80. England PH. End of Life Care Economic Tool. 9 February 2017. URL: www.gov.uk/government/publications/end-of-life-care-economic-tool (accessed 23 March 2023).
  81. Amdahl J, Diaz J, Sharma A, Park J, Chandiwana D, Delea TE. Cost-effectiveness of pazopanib versus sunitinib for metastatic renal cell carcinoma in the United Kingdom. PLOS ONE 2017;12(6):e0175920. doi: 10.1371/journal.pone.0175920. [DOI] [PMC free article] [PubMed]
  82. Zhang W, Bansback N, Anis AH. Measuring and valuing productivity loss due to poor health: a critical review. Soc Sci Med 2011;72(2):185–92. doi: 10.1016/j.socscimed.2010.10.026. [DOI] [PubMed]
  83. Statistics OfN. Employee Earnings in the UK: 2020. 3 November 2020. URL: https://www.ons.gov.uk/employmentandlabourmarket/peopleinwork/earningsandworkinghours/bulletins/annualsurveyofhoursandearnings/2020 (accessed 23 March 2023).
  84. Koopmanschap MA, Rutten FF, van Ineveld BM, van Roijen L. The friction cost method for measuring indirect costs of disease. J Health Econ 1995;14(2):171–89. doi: 10.1016/0167-6296(94)00044-5. [DOI] [PubMed]
  85. Willan AR, Lin DY, Manca A. Regression methods for cost-effectiveness analysis with censored data. Stat Med 2005;24(1):131–45. doi: 10.1002/sim.1794. [DOI] [PubMed]
  86. Barton GR, Briggs AH, Fenwick EA. Optimal cost-effectiveness decisions: the role of the cost-effectiveness acceptability curve (CEAC), the cost-effectiveness acceptability frontier (CEAF), and the expected value of perfection information (EVPI). Value Health 2008;11(5):886–97. doi: 10.1111/j.1524-4733.2008.00358.x. [DOI] [PubMed]
  87. Claxton K, Martin S, Soares M, Rice N, Spackman E, Hinde S, et al. Methods for the estimation of the National Institute for Health and Care Excellence cost-effectiveness threshold. Health Technol Assess 2015;19(14):1–504. doi: 10.3310/hta19140. [DOI] [PMC free article] [PubMed]
  88. Bullement A, Cranmer HL, Shields GE. A review of recent decision-analytic models used to evaluate the economic value of cancer treatments. Appl Health Econ Health Policy 2019;17(6):771–80. doi: 10.1007/s40258-019-00513-3. [DOI] [PMC free article] [PubMed]
  89. National Institute for Health and Care Excellence (NICE). Pazopanib (Votrient) for the First-line Treatment of Patients with Advanced Renal Cell Carcinoma (RCC). 16 April 2010. URL: www.nice.org.uk/guidance/ta215/documents/renal-cell-carcinoma-first-line-metastatic-pazopanib-manufacturer-submission-submission2.
  90. Latimer NR. Survival analysis for economic evaluations alongside clinical trials – extrapolation with patient-level data: inconsistencies, limitations, and a practical guide. Med Decis Making 2013;33(6):743–54. doi: 10.1177/0272989X12472398. [DOI] [PubMed]
  91. Edlin R, McCabe C, Hulme P, Wright J. Cost Effectiveness Modelling for Health Technology Assessment: A Practical Course. New York: Springer; 2015.
  92. Claxton KP, Sculpher MJ. Using value of information analysis to prioritise health research: some lessons from recent UK experience. PharmacoEconomics 2006;24(11):1055–68. doi: 10.2165/00019053-200624110-00003. [DOI] [PubMed]
  93. Strong M, Oakley JE, Brennan A. Estimating multiparameter partial expected value of perfect information from a probabilistic sensitivity analysis sample: a nonparametric regression approach. Med Decis Making 2014;34(3):311–26. doi: 10.1177/0272989X13505910. [DOI] [PMC free article] [PubMed]
  94. O’Cathain A, Thomas KJ, Drabble SJ, Rudolph A, Goode J, Hewison J. Maximising the value of combining qualitative research and randomised controlled trials in health research: the QUAlitative Research in Trials (QUART) study – a mixed methods study. Health Technol Assess 2014;18(38):1v–197vi. doi: 10.3310/hta18380. [DOI] [PMC free article] [PubMed]
  95. Hewison J, Haines A. Overcoming barriers to recruitment in health research. BMJ 2006;333(7562):300–2. doi: 10.1136/bmj.333.7562.300. [DOI] [PMC free article] [PubMed]
  96. QSR International Pty Ltd. NVivo 2015 version 11 computer programme; 2015.
  97. Boyatzis RE. Transforming Qualitative Information: Thematic Analysis and Code Development. London: SAGE Publications Ltd; 1998.
  98. Hoffe H YJ, Marks David F, Yardley LucyResearch Methods for Clinical and Health Psychology. London: SAGE Publications Ltd; 2004.
  99. Boyatzis RE. Transforming Qualitative Information. London: SAGE Publications Ltd; 1988.
  100. McCann SK, Campbell MK, Entwistle VA. Reasons for participating in randomised controlled trials: conditional altruism and considerations for self. Trials 2010;11:31. doi: 10.1186/1745-6215-11-31. [DOI] [PMC free article] [PubMed]
  101. Lane JA, Donovan JL, Davis M, Walsh E, Dedman D, Down L, et al.; ProtecT study group. Active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and diagnostic and baseline results of the ProtecT randomised phase 3 trial. Lancet Oncol 2014;15(10):1109–18. doi: 10.1016/S1470-2045(14)70361-4. [DOI] [PubMed]
  102. Rooshenas L, Paramasivan S, Jepson M, Donovan JL. Intensive triangulation of qualitative research and quantitative data to improve recruitment to randomized trials: The QuinteT approach. Qual Health Res 2019;29(5):672–9. doi: 10.1177/1049732319828693. [DOI] [PubMed]
  103. Zhong J, Palkhi E, Buckley DL, Collinson FJ, Ralph C, Jagdev S, et al. Feasibility study on using dynamic contrast enhanced MRI to assess the effect of tyrosine kinase inhibitor therapy within the star trial of metastatic renal cell cancer. Diagnostics (Basel) 2021;11(7):1302. doi: 10.3390/diagnostics11071302. [DOI] [PMC free article] [PubMed]
  104. Hahn OM, Yang C, Medved M, Karczmar G, Kistner E, Karrison T, et al. Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma. J Clin Oncol 2008;26(28):4572–8. doi: 10.1200/JCO.2007.15.5655. [DOI] [PMC free article] [PubMed]
  105. Sweis RF, Medved M, Towey S, Karczmar GS, Oto A, Szmulewitz RZ, et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic biomarker for pazopanib in metastatic renal carcinoma. Clin Genitourin Cancer 2017;15(2):207–12. doi: 10.1016/j.clgc.2016.08.011. [DOI] [PMC free article] [PubMed]
  106. Bex A, Fournier L, Lassau N, Mulders P, Nathan P, Oyen WJ, Powles T. Assessing the response to targeted therapies in renal cell carcinoma: technical insights and practical considerations. Eur Urol 2014;65(4):766–77. doi: 10.1016/j.eururo.2013.11.031. [DOI] [PubMed]
  107. Rossi SH, Prezzi D, Kelly-Morland C, Goh V. Imaging for the diagnosis and response assessment of renal tumours. World J Urol 2018;36(12):1927–42. doi: 10.1007/s00345-018-2342-3. [DOI] [PMC free article] [PubMed]
  108. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al.; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372(9637):449–56. doi: 10.1016/S0140-6736(08)61039-9. [DOI] [PubMed]
  109. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al.; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373(19):1814–23. doi: 10.1056/NEJMoa1510016. [DOI] [PMC free article] [PubMed]
  110. McDermott DF, Drake CG, Sznol M, Choueiri TK, Powderly JD, Smith DC, et al. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving Nivolumab. J Clin Oncol 2015;33(18):2013–20. doi: 10.1200/JCO.2014.58.1041. [DOI] [PMC free article] [PubMed]
  111. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, et al. 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;24(1):16–24. doi: 10.1200/JCO.2005.02.2574. [DOI] [PubMed]
  112. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228–47. doi: 10.1016/j.ejca.2008.10.026. [DOI] [PubMed]
  113. Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 2007;25(13):1753–9. doi: 10.1200/JCO.2006.07.3049. [DOI] [PubMed]
  114. van der Veldt AA, Meijerink MR, van den Eertwegh AJ, Haanen JB, Boven E. Choi response criteria for early prediction of clinical outcome in patients with metastatic renal cell cancer treated with sunitinib. Br J Cancer 2010;102(5):803–9. doi: 10.1038/sj.bjc.6605567. [DOI] [PMC free article] [PubMed]
  115. Nathan PD, Vinayan A, Stott D, Juttla J, Goh V. CT response assessment combining reduction in both size and arterial phase density correlates with time to progression in metastatic renal cancer patients treated with targeted therapies. Cancer Biol Ther 2010;9(1):15–9. doi: 10.4161/cbt.9.1.10340. [DOI] [PubMed]
  116. Thian Y, Gutzeit A, Koh DM, Fisher R, Lote H, Larkin J, Sohaib A. Revised Choi imaging criteria correlate with clinical outcomes in patients with metastatic renal cell carcinoma treated with sunitinib. Radiology 2014;273(2):452–61. doi: 10.1148/radiol.14132702. [DOI] [PubMed]
  117. Smith AD, Lieber ML, Shah SN. Assessing tumor response and detecting recurrence in metastatic renal cell carcinoma on targeted therapy: importance of size and attenuation on contrast-enhanced CT. AJR Am J Roentgenol 2010;194(1):157–65. doi: 10.2214/AJR.09.2941. [DOI] [PubMed]
  118. Smith AD, Shah SN, Rini BI, Lieber ML, Remer EM. Morphology, Attenuation, Size, and Structure (MASS) criteria: assessing response and predicting clinical outcome in metastatic renal cell carcinoma on antiangiogenic targeted therapy. AJR Am J Roentgenol 2010;194(6):1470–8. doi: 10.2214/AJR.09.3456. [DOI] [PubMed]
  119. Krajewski KM, Nishino M, Franchetti Y, Ramaiya NH, Van den Abbeele AD, Choueiri TK. Intraobserver and interobserver variability in computed tomography size and attenuation measurements in patients with renal cell carcinoma receiving antiangiogenic therapy: implications for alternative response criteria. Cancer 2014;120(5):711–21. doi: 10.1002/cncr.28493. [DOI] [PMC free article] [PubMed]
  120. Jain Y, Liew S, Taylor MB, Bonington SC. Is dual-phase abdominal CT necessary for the optimal detection of metastases from renal cell carcinoma? Clin Radiol 2011;66(11):1055–9. doi: 10.1016/j.crad.2011.06.002. [DOI] [PubMed]
  121. Goh V, Ganeshan B, Nathan P, Juttla JK, Vinayan A, Miles KA. Assessment of response to tyrosine kinase inhibitors in metastatic renal cell cancer: CT texture as a predictive biomarker. Radiology 2011;261(1):165–71. doi: 10.1148/radiol.11110264. [DOI] [PubMed]
  122. Haider MA, Vosough A, Khalvati F, Kiss A, Ganeshan B, Bjarnason GA. CT texture analysis: a potential tool for prediction of survival in patients with metastatic clear cell carcinoma treated with sunitinib. Cancer Imaging 2017;17(1):4. doi: 10.1186/s40644-017-0106-8. [DOI] [PMC free article] [PubMed]
  123. Gillies RJ, Kinahan PE, Hricak H. Radiomics: images are more than pictures, they are data. Radiology 2016;278(2):563–77. doi: 10.1148/radiol.2015151169. [DOI] [PMC free article] [PubMed]
  124. Aerts HJ, Velazquez ER, Leijenaar RT, Parmar C, Grossmann P, Carvalho S, et al. Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach. Nat Commun 2014;5:4006. doi: 10.1038/ncomms5006. [DOI] [PMC free article] [PubMed]
  125. Collinson FJ, Gregory WM, McCabe C, Howard H, Lowe C, Potrata D, et al. The STAR trial protocol: a randomised multi-stage phase II/III study of Sunitinib comparing temporary cessation with allowing continuation, at the time of maximal radiological response, in the first-line treatment of locally advanced/metastatic renal cancer. BMC Cancer 2012;12:598. doi: 10.1186/1471-2407-12-598. [DOI] [PMC free article] [PubMed]
  126. Zwanenburg A, Vallieres M, Abdalah MA, Aerts H, Andrearczyk V, Apte A, et al. The image biomarker standardization initiative: standardized quantitative radiomics for high-throughput image-based phenotyping. Radiology 2020;295(2):328–38. doi: 10.1148/radiol.2020191145. [DOI] [PMC free article] [PubMed]
  127. Thiam R, Fournier LS, Trinquart L, Medioni J, Chatellier G, Balvay D, et al. Optimizing the size variation threshold for the CT evaluation of response in metastatic renal cell carcinoma treated with sunitinib. Ann Oncol 2010;21(5):936–41. doi: 10.1093/annonc/mdp466. [DOI] [PubMed]
  128. Oudard S, Thiam R, Fournier LS, Medioni J, Lamuraglia M, Scotte F, et al. Optimisation of the tumour response threshold in patients treated with everolimus for metastatic renal cell carcinoma: analysis of response and progression-free survival in the RECORD-1 study. Eur J Cancer 2012;48(10):1512–8. doi: 10.1016/j.ejca.2012.01.027. [DOI] [PubMed]
  129. Krajewski KM, Franchetti Y, Nishino M, Fay AP, Ramaiya N, Van den Abbeele AD, Choueiri TK. 10% Tumor diameter shrinkage on the first follow-up computed tomography predicts clinical outcome in patients with advanced renal cell carcinoma treated with angiogenesis inhibitors: a follow-up validation study. Oncologist 2014;19(5):507–14. doi: 10.1634/theoncologist.2013-0391. [DOI] [PMC free article] [PubMed]
  130. Krajewski KM, Guo M, Van den Abbeele AD, Yap J, Ramaiya N, Jagannathan J, et al. Comparison of four early posttherapy imaging changes (EPTIC; RECIST 1.0, tumor shrinkage, computed tomography tumor density, Choi criteria) in assessing outcome to vascular endothelial growth factor-targeted therapy in patients with advanced renal cell carcinoma. Eur Urol 2011;59(5):856–62. doi: 10.1016/j.eururo.2011.01.038. [DOI] [PubMed]
  131. Smith AD, Zhang X, Bryan J, Souza F, Roda M, Sirous R, et al. Vascular tumor burden as a new quantitative CT biomarker for predicting metastatic RCC response to antiangiogenic therapy. Radiology 2016;281(2):484–98. doi: 10.1148/radiol.2016160143. [DOI] [PubMed]
  132. Hudson JM, Bailey C, Atri M, Stanisz G, Milot L, Williams R, et al. The prognostic and predictive value of vascular response parameters measured by dynamic contrast-enhanced-CT, -MRI and -US in patients with metastatic renal cell carcinoma receiving sunitinib. Eur Radiol 2018;28(6):2281–90. doi: 10.1007/s00330-017-5220-2. [DOI] [PubMed]
  133. Matoori S, Thian Y, Koh DM, Sohaib A, Larkin J, Pickering L, Gutzeit A. Contrast-enhanced CT density predicts response to sunitinib therapy in metastatic renal cell carcinoma patients. Transl Oncol 2017;10(4):679–85. doi: 10.1016/j.tranon.2017.06.001. [DOI] [PMC free article] [PubMed]
  134. Hahn S. Understanding noninferiority trials. Korean J Pediatr 2012;55(11):403–7. doi: 10.3345/kjp.2012.55.11.403. [DOI] [PMC free article] [PubMed]
  135. Chibaudel B, Bonnetain F, Shi Q, Buyse M, Tournigand C, Sargent DJ, et al. Alternative end points to evaluate a therapeutic strategy in advanced colorectal cancer: evaluation of progression-free survival, duration of disease control, and time to failure of strategy – an Aide et Recherche en Cancerologie Digestive Group Study. J Clin Oncol 2011;29(31):4199–204. doi: 10.1200/JCO.2011.35.5867. [DOI] [PubMed]
  136. Head SJ, Kaul S, Bogers AJJC, Kappetein AP. Non-inferiority study design: lessons to be learned from cardiovascular trials. Eur Heart J 2012;33(11):1318–24. doi: 10.1093/eurheartj/ehs099. [DOI] [PubMed]
  137. Motzer RJTN, McDermott DF, Burotto M, Choueiri TK, Hammers HJ, Plimack ER, et al. Conditional Survival and 5-Year Follow-up in CheckMate 214: First-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in Advanced Renal Cell Carcinoma (aRCC). European Society for Medical Oncology; 16 Sep 2021. Paris: European Society for Medical Oncology; 2021. doi: 10.1016/j.annonc.2024.07.727. [DOI] [PubMed]
  138. MRC Clinical Trials Unit. REFINE: REduced Frequency ImmuNE Checkpoint Inhibition in Cancers: University College London. 2021. URL: www.ctu.mrc.ac.uk/studies/all-studies/r/refine/ (accessed 28 June 2021).
  139. Coen O, Corrie P, Marshall H, Plummer R, Ottensmeier C, Hook J, et al. The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma. BMC Cancer 2021;21(1):761. doi: 10.1186/s12885-021-08509-w. [DOI] [PMC free article] [PubMed]

RESOURCES