Response to treatment

The purpose of this page is to create a central repository of general and disease-specific response criteria. These are divided into three categories: strong, intermediate, and weak endpoints. See the Levels of Evidence page and individual page's response criteria sections for more details.

Strong ("hard") endpoints

• Overall survival (OS)
• All-cause mortality
• Disease-specific mortality

Intermediate surrogate endpoints

These are almost all measures of time interval between diagnosis and/or start of treatment, and a predefined event such as cancer recurrence, cancer progression, or a composite outcome. We will expand this section over time, including adding literature that supports the use of a surrogate end point for disease-specific scenarios. These types of endpoints are generally evaluated using a nonparametric test such as log-rank or a survival model such as Cox proportional hazards model.

Distant metastasis-free survival (DMFS)

References

1. Rotolo F, Pignon JP, Bourhis J, Marguet S, Leclercq J, Tong Ng W, Ma J, Chan AT, Huang PY, Zhu G, Chua DT, Chen Y, Mai HQ, Kwong DL, Soong YL, Moon J, Tung Y, Chi KH, Fountzilas G, Zhang L, Hui EP, Lee AW, Blanchard P, Michiels S; MAC-NPC Collaborative Group. Surrogate End Points for Overall Survival in Loco-Regionally Advanced Nasopharyngeal Carcinoma: An Individual Patient Data Meta-analysis. J Natl Cancer Inst. 2017 Apr;109(4). link to original article link to PMC article PubMed

Disease-free survival (DFS)

Defined as the time from randomization to the first event of either recurrent disease or death.

References

1. Sargent DJ, Wieand HS, Haller DG, Gray R, Benedetti JK, Buyse M, Labianca R, Seitz JF, O'Callaghan CJ, Francini G, Grothey A, O'Connell M, Catalano PJ, Blanke CD, Kerr D, Green E, Wolmark N, Andre T, Goldberg RM, De Gramont A. Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2005 Dec 1;23(34):8664-70. Epub 2005 Oct 31. link to original article PubMed
2. Sargent DJ, Patiyil S, Yothers G, Haller DG, Gray R, Benedetti J, Buyse M, Labianca R, Seitz JF, O'Callaghan CJ, Francini G, Grothey A, O'Connell M, Catalano PJ, Kerr D, Green E, Wieand HS, Goldberg RM, de Gramont A; ACCENT Group. End points for colon cancer adjuvant trials: observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group. J Clin Oncol. 2007 Oct 10;25(29):4569-74. Epub 2007 Sep 17. link to original article PubMed

Event-free survival (EFS)

Events sometimes defined differently, but usually include relapse, progression, and death from any cause.

References

1. Maurer MJ, Ghesquières H, Jais JP, Witzig TE, Haioun C, Thompson CA, Delarue R, Micallef IN, Peyrade F, Macon WR, Jo Molina T, Ketterer N, Syrbu SI, Fitoussi O, Kurtin PJ, Allmer C, Nicolas-Virelizier E, Slager SL, Habermann TM, Link BK, Salles G, Tilly H, Cerhan JR. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol. 2014 Apr 1;32(10):1066-73. Epub 2014 Feb 18. link to PMC article PubMed

Failure-free survival (FFS)

Defined as the absence of an additional systemic therapy, relapse, or non-relapse mortality.

Invasive disease free survival (IDFS)

In breast cancer, defined as time from randomization to local recurrence after mastectomy, invasive local recurrence in the ipsilateral breast after lumpectomy, regional recurrence, distant recurrence, invasive contralateral breast cancer, second primary cancer (other than squamous or basal cell carcinoma of the skin, melanoma in situ, or carcinoma in situ), or death as a result of any cause before recurrence or second primary cancer.

Progression-free survival (PFS)

The most commonly used surrogate time-based measure.

References

General

1. Belin L, Tan A, De Rycke Y, Dechartres A. Progression-free survival as a surrogate for overall survival in oncology trials: a methodological systematic review. Br J Cancer. 2020 May;122(11):1707-1714. Epub 2020 Mar 26. link to original article PubMed

Breast cancer

1. Burzykowski T, Buyse M, Piccart-Gebhart MJ, Sledge G, Carmichael J, Lück HJ, Mackey JR, Nabholtz JM, Paridaens R, Biganzoli L, Jassem J, Bontenbal M, Bonneterre J, Chan S, Basaran GA, Therasse P. Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J Clin Oncol. 2008 Apr 20;26(12):1987-92. link to original article PubMed

Colorectal cancer

1. Tang PA, Bentzen SM, Chen EX, Siu LL. Surrogate end points for median overall survival in metastatic colorectal cancer: literature-based analysis from 39 randomized controlled trials of first-line chemotherapy. J Clin Oncol. 2007 Oct 10;25(29):4562-8. Epub 2007 Sep 17. link to original article PubMed
2. Buyse M, Burzykowski T, Carroll K, Michiels S, Sargent DJ, Miller LL, Elfring GL, Pignon JP, Piedbois P. Progression-free survival is a surrogate for survival in advanced colorectal cancer. J Clin Oncol. 2007 Nov 20;25(33):5218-24. link to original article PubMed

Diffuse large B-cell lymphoma

1. Shi Q, Schmitz N, Ou FS, Dixon JG, Cunningham D, Pfreundschuh M, Seymour JF, Jaeger U, Habermann TM, Haioun C, Tilly H, Ghesquieres H, Merli F, Ziepert M, Herbrecht R, Flament J, Fu T, Coiffier B, Flowers CR. Progression-free survival as a surrogate end point for overall survival in first-line diffuse large B-cell lymphoma: an individual patient-level analysis of multiple randomized trials (SEAL). J Clin Oncol. 2018 Sep 1;36(25):2593-2602. Epub 2018 Jul 5. link to original article PubMed

Hepatocellular carcinoma

1. Llovet JM, Montal R, Villanueva A. Randomized trials and endpoints in advanced HCC: role of PFS as a surrogate of survival. J Hepatol. 2019 Jun;70(6):1262-1277. Epub 2019 Mar 31. link to original article PubMed

Malignant pleural mesothelioma

1. Wang X, Wang X, Hodgson L, George SL, Sargent DJ, Foster NR, Ganti AK, Stinchcombe TE, Crawford J, Kratzke R, Adjei AA, Kindler HL, Vokes EE, Pang H. Validation of progression-free survival as a surrogate endpoint for overall survival in malignant mesothelioma: analysis of Cancer and Leukemia Group B and North Central Cancer Treatment Group (Alliance) trials. Oncologist. 2017 Feb;22(2):189-198. Epub 2017 Feb 10. link to PMC article PubMed

Nasopharyngeal carcinoma

1. Rotolo F, Pignon JP, Bourhis J, Marguet S, Leclercq J, Tong Ng W, Ma J, Chan AT, Huang PY, Zhu G, Chua DT, Chen Y, Mai HQ, Kwong DL, Soong YL, Moon J, Tung Y, Chi KH, Fountzilas G, Zhang L, Hui EP, Lee AW, Blanchard P, Michiels S; MAC-NPC Collaborative Group. Surrogate End Points for Overall Survival in Loco-Regionally Advanced Nasopharyngeal Carcinoma: An Individual Patient Data Meta-analysis. J Natl Cancer Inst. 2017 Apr;109(4). link to original article link to PMC article PubMed

Ovarian cancer

1. Sjoquist KM, Lord SJ, Friedlander ML, John Simes R, Marschner IC, Lee CK. Progression-free survival as a surrogate endpoint for overall survival in modern ovarian cancer trials: a meta-analysis. Ther Adv Med Oncol. 2018 Aug 6;10:1758835918788500. eCollection 2018. link to original article link to PMC article PubMed

Relapse-free interval (RFI)

Not commonly used outside of the adjuvant setting. Essentially synonymous with relapse-free survival.

Recurrence- or Relapse-free survival (RFS)

Not commonly used outside of the adjuvant setting. May have slightly varied definitions:

• Defined as the interval from date of randomization to first evidence of recurrence
• Defined as the interval from study entry until local recurrence, distant relapse, or death without relapse, whichever occurrs first

References

1. Suciu S, Eggermont AMM, Lorigan P, Kirkwood JM, Markovic SN, Garbe C, Cameron D, Kotapati S, Chen TT, Wheatley K, Ives N, de Schaetzen G, Efendi A, Buyse M. Relapse-free survival as a surrogate for overall survival in the evaluation of stage II-III melanoma adjuvant therapy. J Natl Cancer Inst. 2018 Jan 1;110(1). link to original article PubMed

Weak surrogate endpoints

This category includes all surrogate measures that are based on objective response to treatment, without a patient-specific survival component. The most frequently reported weak surrogate endpoint in non-randomized trials is the objective response rate (ORR), usually using the RECIST criteria. Note that many of these weak surrogate endpoints have been correlated with survival endpoints, with the general maxim being patients who respond to therapy are more likely to achieve remission, remain in remission, and therefore have a longer cancer-specific and overall survival. Regardless, we annotate RCTs by their stated primary endpoint, unless the primary endpoint is positive AND a stronger secondary endpoint has a statistically significant finding.

CR30

Defined as a complete remission status at the fixed time interval of 30 months after initiation of induction therapy.

References

1. Shi Q, Flowers CR, Hiddemann W, Marcus R, Herold M, Hagenbeek A, Kimby E, Hochster H, Vitolo U, Peterson BA, Gyan E, Ghielmini M, Nielsen T, De Bedout S, Fu T, Valente N, Fowler NH, Hoster E, Ladetto M, Morschhauser F, Zucca E, Salles G, Sargent DJ. Thirty-month complete response as a surrogate end point in first-line follicular lymphoma therapy: an individual patient-level analysis of multiple randomized trials. J Clin Oncol. 2017 Feb 10;35(5):552-560. Epub 2016 Dec 28. link to original article PubMed

General response rates

• Response rate (RR) A generic term that can be any of the below
• Objective or overall response rate (ORR) Definition may vary across cancer subtypes but usually this is a sum of the CR + PR rates.
• Disease control rate (DCR) Usually this is the sum of the CR + PR + SD rates.
• Clinical benefit rate (CBR) Variably defined, but generally accounts for measures of clinical improvement (e.g., less pain, increased function) rather than measures of tumor size change.
• Clinical feasibility rate Defined as no grade 4 neutropenia/thrombocytopenia or thrombocytopenia with bleeding, no grade 3/4 febrile neutropenia or non-hematological toxicity; no premature withdrawal/death.

Morphologic response rates

• Definitions may vary across cancer subtypes:
  • Complete response rate (CR rate)
  • Minimal response rate (MR rate)
  • Partial response rate (PR rate)
  • Stable disease rate (SD rate)
  • Unconfirmed complete response rate (CRu rate)

RECIST criteria

• RECIST 1.1: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. PubMed
• iRECIST: Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litière S, Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella C, de Vries EG; RECIST working group. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017 Mar;18(3):e143-e152. Epub 2017 Mar 2. link to original article link to PMC article PubMed
• imRECIST: Hodi FS, Ballinger M, Lyons B, Soria JC, Nishino M, Tabernero J, Powles T, Smith D, Hoos A, McKenna C, Beyer U, Rhee I, Fine G, Winslow N, Chen DS, Wolchok JD. Immune-modified Response Evaluation Criteria In Solid Tumors (imRECIST): refining guidelines to assess the clinical benefit of cancer immunotherapy. J Clin Oncol. 2018 Mar 20;36(9):850-858. Epub 2018 Jan 17. link to original article PubMed
• itRECIST: Goldmacher GV, Khilnani AD, Andtbacka RHI, Luke JJ, Hodi FS, Marabelle A, Harrington K, Perrone A, Tse A, Madoff DC, Schwartz LH. Response Criteria for Intratumoral Immunotherapy in Solid Tumors: itRECIST. J Clin Oncol. 2020 Aug 10;38(23):2667-2676. Epub 2020 Jun 18. link to original article link to PMC article PubMed

Neoadjuvant response rates

• Good response rate
  • In Breast cancer, a score of 3, 4, or 5 on the Miller-Payne scoring system
• Objective clinical response (OCR rate)
• Pathologic complete response rate (pCR rate)

Overall survival at x months (OSx)

Defined as the proportion of patients who are alive at x months (e.g., OS12, OS60).

Progression-free survival at x months (PFSx)

Defined as the proportion of patients who are progression-free at x months (e.g., PFS12, PFS24, PFS36).

Progression-free survival, median (PFS50%)

Defined as the period of time until half (50%) of the patients have had a progression-free survival event.

Condition-specific endpoints

Breast cancer

• 2023: Standardized Definitions for Efficacy End Points in Neoadjuvant Breast Cancer Clinical Trials: NeoSTEEP link to PMC article PubMed
• 2021: Standardized Definitions for Efficacy End Points (STEEP) criteria 2.0 link to PMC article PubMed

• 2007: Standardized Definitions for Efficacy End Points (STEEP) criteria 1.0 link to original article PubMed

Glioma

• Response Assessment in Neuro-Oncology (RANO) criteria (2010)

Hematologic malignancies

• Complete response with incomplete hematologic recovery (CR_i)
• Complete response without minimal residual disease (CR_MRD-)
• Complete response with minimal residual disease (CR_MRD+)
• Major cytogenetic reponse (MCyR)
• Major hematologic response (MaHR)
• Minor hematologic response (MiHR)
• Overall hematologic response (OHR)

Acute leukemia

• Leukemia-free survival (LFS)
• Morphologic leukemia-free state (MLFS)
• No evidence of leukemia (NEL)
• Primary refractory disease
  • In leukemia, generally refers to the failure to achieve CR or CR_i after two courses of intensive induction.

Chronic myeloid leukemia

Hematologic response (HR)

• Partial hematologic response (PHR)
• Complete hematologic response (CHR) per ELN 2013 recommendations must meet ALL of the following:
  • Platelets less than 450 x10⁹/L
  • WBC count less than 10 x10⁹/L
  • No circulating immature myeloid cells
  • Less than 5% basophils on differential
  • No palpable splenomegaly

Cytogenetic response

• Major cytogenetic response (MCR or MCyR): Ph+ cells are detectable but less than 35% of bone marrow cells
• Complete cytogenetic response (CCR or CCyR or CCgR): No Ph+ cells are detectable by FISH or cytogenetics

Molecular response

• Major mol­ecular response (MMR): International Scale (IS) BCR-ABL by PCR is less than or equal to 0.10%
• MR^4.0: International Scale (IS) BCR-ABL by PCR is less than 0.01%
• MR^4.5: International Scale (IS) BCR-ABL by PCR is less than 0.0032%
• Mol­ecular­ly un­detect­able leukemia: BCR-ABL tran­scripts are non-quant­ifiable and non-detect­able by PCR

Multiple myeloma

• Near complete response (nCR)
• Stringent complete response rate (sCR)
• Very good partial response rate (VGPR)

Neuroblastoma

• International Neuroblastoma Response Criteria (INRC) (2017)

Pediatric ALL

• International consensus of the Ponte-di-Legno Consortium (2022)