Progression-free survival

Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse".[1] In oncology, PFS usually refers to situations in which a tumor is present, as demonstrated by laboratory testing, radiologic testing, or clinically. Similarly, "disease-free survival" is the length of time after patients have received treatment and have no detectable disease.

Time to progression (TTP) does not count patients who die from other causes but is otherwise a close equivalent to PFS (unless there are many such events).[2] The FDA gives separate definitions and prefers PFS.[3]

Background

PFS is widely used as a surrogate endpoint in oncology.[4] The definition of "progression" generally involves imaging techniques (plain radiograms, CT scans, MRI, PET scans, ultrasounds) or other aspects: biochemical progression may be defined on the basis of an increase in a tumor marker (such as CA125 for epithelial ovarian cancer or PSA for prostate cancer). In clinical trials, what precisely constitutes an "event" in PFS (an event being either disease progression or death) may vary depending on the specific disease and/or the toxicological characteristics of the treatments in the trial; however, this is generally defined in the trial protocol prior to the trial enrolling patients.

As of 2019, change in the radiological aspects of a lesion is defined according to RECIST criteria. Progression may also be due to the appearance of a new lesion or to unequivocal progression in other lesions, such as an increase in size or the lesions spreading to nearby tissues.

Progression-free survival is commonly used as an alternative to overall survival (OS). In some cancers, PFS and OS are strictly related, but in others they are not. In a time trade off study in renal cancer, physicians rated PFS the most important aspect of treatment, while for patients it fell below fatigue, hand foot syndrome, and other toxicities. <Park et al.>

Special aspects

By definition, PFS refers to the date on which progression is detected. An advantage of measuring PFS over measuring OS is that PFS appears sooner than deaths, allowing faster trials. PFS also allows for greater insight into consequences of diseases and treatments that fall below the threshold of mortality, such as pain, organ dysfunction, interference in daily life, and other effects that progressive disease may have on the patient while they are still alive.

The use of PFS for proof of effectiveness and regulatory approval is controversial. It is often used as a clinical endpoint in randomized controlled trials for cancer therapies.[5] It is a metric frequently used by the UK National Institute for Health and Clinical Excellence[6] and the U.S. Food and Drug Administration to evaluate the effectiveness of a cancer treatment. Studies find that new cancer drugs approved by the U.S. Food and Drug Administration improve progression-free survival by a median of 2 to 3 months depending on the sample and analyzed time period: 2.5 months,[7] 2.70 months,[8] 3.30 months.[9]

PFS improvements do not always result in corresponding improvements in overall survival, and the control of the disease may come at the biological expense of side effects from the treatment itself.[10] This has been described as an example of the McNamara fallacy.[10][11]

See also

References
  1. "NCI Dictionary of Cancer Terms". National Cancer Institute.
  2. "Progression-free survival and time to progression as primary end points in advanced breast cancer: often used, sometimes loosely defined". Archived from the original on 2015-06-12. {{cite journal}}: Cite journal requires |journal= (help)
  3. "Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics" (PDF). Food and Drug Administration. 25 January 2021.
  4. Dancey JE, Dodd LE, Ford R, et al. (2009). "Recommendations for the assessment of progression in randomised cancer treatment trials". Eur. J. Cancer. 45 (2): 281–9. doi:10.1016/j.ejca.2008.10.042. PMID 19097775.
  5. "Progression-free survival (PFS) and time to progression (TTP) as surrogate endpoints for median overall survival (mOS) in metastatic colorectal cancer (MCRC): Analysis from 34 randomized controlled trials (RCTs) of first-line chemotherapy". {{cite journal}}: Cite journal requires |journal= (help)
  6. BMJ 31-Jan-2009 "NICE and the challenge of cancer drugs" p271
  7. Fojo T, Mailankody S, Lo A (2014). "Unintended Consequences of Expensive Cancer Therapeutics—The Pursuit of Marginal Indications and a Me-Too Mentality That Stifles Innovation and Creativity: The John Conley Lecture". JAMA Otolaryngol Head Neck Surg. 140 (12): 1225–1236. doi:10.1001/jamaoto.2014.1570. PMID 25068501.
  8. Ladanie A, Schmitt AM, Speich B, Naudet F, Agarwal A, Pereira TV, Sclafani F, Herbrand AK, Briel M, Martin-Liberal J, Schmid T, Ewald H, Ioannidis JP, Bucher HC, Kasenda B, Hemkens LG (2020). "Clinical Trial Evidence Supporting US Food and Drug Administration Approval of Novel Cancer Therapies Between 2000 and 2016". JAMA Netw Open. 3 (11): e2024406. doi:10.1001/jamanetworkopen. PMID 33170262.
  9. Michaeli DT, Michaeli T (2022). "Overall Survival, Progression-Free Survival, and Tumor Response Benefit Supporting Initial US Food and Drug Administration Approval and Indication Extension of New Cancer Drugs, 2003-2021". Journal of Clinical Oncology. doi:10.1200/JCO.22.00535. PMID 35921606.
  10. Booth, Christopher M.; Eisenhauer, Elizabeth A. (2012). "Progression-Free Survival: Meaningful or Simply Measurable?". Journal of Clinical Oncology. 30 (10): 1030–1033. doi:10.1200/JCO.2011.38.7571. PMID 22370321.
  11. Basler, Michael H. (2009). "Utility of the McNamara fallacy". BMJ. 339: b3141. doi:10.1136/bmj.b3141. S2CID 71916631.
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