- Adjuvant treatment efficacy can be assessed only at a future point, based on tumor recurrence. Thus, risk–benefit assessments in the curative setting are necessarily blind.
- Adjuvant trials must determine whether offering the treatment early, compared with at the time of relapse, offers clinical benefit.
- For adjuvant trials, overall survival benefit against a control arm with adequate crossover at the time of relapse is the most accurate indicator of patient benefit.
Disease-free survival (DFS) is one of the most complicated endpoints in oncology. Unlike progression-free survival in the advanced cancer setting, which refers to time from treatment to disease progression (or death) in patients who already have measurable cancer in their bodies, DFS refers to time from treatment until the recurrence of disease (or death) after undergoing curative-intent treatment. This distinction is important because, unlike in the advanced setting where treatment response can be measured quickly using imaging or tumor markers, treating a patient in the curative setting is blind by definition; adjuvant treatment efficacy can be assessed only at a distant point in the future, based on whether the tumor recurred. Hence, risk–benefit assessments in the curative setting are not straightforward, and a drug showing improved DFS alone may not always be in patients' best interests.1
In the adjuvant setting, where DFS is used as an endpoint in clinical trials, the risks of therapies are immediate. Moreover, there is a guarantee that treatment in this context will impair quality of life (QOL); in the absence of cancer and cancer symptoms, it is not possible for treatment to improve QOL. Although risks are virtually certain, any individual patient may or may not derive potential benefit. Some patients will have tumor recurrence despite the new treatment, and some patients will not have tumor recurrence even if they did not receive the new treatment. For these two groups of patients, a new adjuvant therapy will not offer benefit—rather, only toxicity. Thus, in an adjuvant setting, we are necessarily overtreating several patients, which is justified only if there is improvement in overall survival (OS) rates.2
Measuring DFS Benefit Against Lack of OS Benefit
DFS improvement in the absence of OS improvement means that similar survival rates can be achieved by using the drug at the time of disease relapse, thus sparing patients who do not relapse from unnecessary physical and financial toxicities (Figure). It is worth emphasizing that the threshold for side effects in the adjuvant context is very different than in the relapsed/advanced setting, where QOL may actually improve with therapy if the burden of disease regresses.
Some treatment toxicities are serious and even fatal. Even if fatal toxicities were to occur in 0.5% of patients, one must consider whether using such a treatment as adjuvant therapy in all patients, many of whom may have never needed it, is justified in the absence of OS benefit. Recent adjuvant oncology trials involve immunotherapies and targeted drugs, and the duration of treatment is usually upwards of 1 year. These regimens are unlike cytotoxic therapies, which are offered for a limited number of cycles. Hence, the therapeutic burden of adjuvant treatment in the modern era has become substantial, and it can be justified only if survival is improved.
Consider the KEYNOTE-564 trial, for example.3 Immunotherapy has already been established as the standard-of-care treatment for advanced renal cell carcinoma. KEYNOTE-564, which tested whether offering the same treatment as adjuvant therapy could provide clinical benefit, demonstrated an improvement in DFS. OS data are immature, and not yet significant. Should this DFS benefit alone change practice? The same question could be asked of atezolizumab (IMpower0104) and osimertinib (ADAURA5) in non–small cell lung cancer.
There are two key points to consider. First, if there is no improvement in OS upon follow up, then giving these treatments as adjuvant therapy is not necessary; these therapies could safely be delivered later, at the time of relapse, thus preventing overtreatment of patients who do not benefit from this treatment early on. Because these treatments are already standard-of-care at advanced stages, these results would imply that offering the treatment at any point is important and that the treatment does not necessarily need to be offered early in the adjuvant setting. For patients whose disease recurs in spite of adjuvant therapy, these results also mean that one important treatment option may no longer be as beneficial because they had already received it.
Second, if there is improvement in OS upon follow up, then it is critical to understand what proportion of patients in the control arm received the treatment at the time of disease relapse. If this proportion is low and not reflective of routine practice, any improvement in OS is therefore not meaningful, because it may simply reflect the fact that patients in the control arm were deprived of standard-of-care therapy at the time of relapse.6 The question that must be answered in adjuvant trials is whether offering the treatment early, compared with at the time of relapse, offers clinical benefit. If the patients in the control arm do not receive this treatment at the time of relapse, the trial is asking instead whether the treatment ever (versus never) offers clinical benefit; this question already has answers based on trials in the advanced setting.
Second, if there is improvement in OS upon follow up, then it is critical to understand what proportion of patients in the control arm received the treatment at the time of disease relapse.
Thus, for adjuvant trials, OS benefit against a control arm with adequate crossover at the time of relapse is the most accurate indicator of patient benefit. There are some caveats to this conclusion. Some patients may place a high value on preventing disease recurrence, despite the toxicities and lack of survival improvement; however, this value could be a result of oncologists not being able to more clearly explain the concepts of surrogate endpoints and treatment benefits. In addition, in settings where DFS has already been validated as an adequate surrogate for OS, DFS benefit can safely be presumed to translate to OS benefit. Examples of where DFS surrogacy has been validated include HER2-positive breast cancer7,8 and stage III colon cancer.9
When treatment options are known to be effective, the natural tendency is to try to use them in earlier lines of therapy. However, earlier aggressive treatment is not necessarily the best treatment, especially when many patients may never need it and when those who do may derive the same benefit by using it at the time of relapse.
- Gyawali B, Prasad V. Making adjuvant therapy decisions with uncertain data. Ann Oncol. 2019;30:361-364
- Gyawali B, West HJ. Lessons From ADAURA on Adjuvant Cancer Drug Trials: Evidence, Ethics, and Economics. J Clin Oncol. 2021;39:175-177
- Choueiri TK, Tomczak P, Park SH, et al; KEYNOTE-564 Investigators. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021;385:683-694
- Wakelee HA, Altorki NK, Zhou C, et al. IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl_15):8500
- Wu YL, Tsuboi M, He J, et al. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2020;383:1711-1723
- Gyawali B, de Vries EGE, Dafni U, et al. Biases in study design, implementation, and data analysis that distort the appraisal of clinical benefit and ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scoring. ESMO Open. 2021;6:100117
- Gyawali B, Hey SP, Kesselheim AS. Evaluating the evidence behind the surrogate measures included in the FDA's table of surrogate endpoints as supporting approval of cancer drugs. EClinicalMedicine. 2020;21:100332
- Saad ED, Squifflet P, Burzykowski T, et al. Disease-free survival as a surrogate for overall survival in patients with HER2-positive, early breast cancer in trials of adjuvant trastuzumab for up to 1 year: a systematic review and meta-analysis. Lancet Oncol. 2019;20:361-370
- Yin J, Salem ME, Dixon JG, et al. Re-Evaluating Disease-Free Survival as an Endpoint vs Overall Survival in Stage III Adjuvant Colon Cancer Trials. J Natl Cancer Inst. 2021;djab187