Is it a cure or nothing for cancer patients?
Is there another way to measure the benefit from any medication?
We all want the cure, the Complete Response (CR) that can lasts many months or years. Often we have to settle for some reduction in our tumors or mets, a Partial Response (PR). But even “Stable Disease” is welcome news. To get that cancer back in its cage, even for a time, is better than “Progressive Disease”. When the cancer is progressing, your life may be regressing, and that isn’t what you want to hear. That Progression Free Survival (PFS) has to start with stopping the cancer.
As complete and durable (ten years) responder to high dose interleukin 2 (HD IL-2), I welcome any discussions of “Clinical Benefit (CB)”. CB includes all the good responses with any cancer treatment, CRs, PRs, and SDs. We and our doctors need this information to make informed decisions about treatment, for IL2 or other meds. The value of Stable Disease has been ignored in many studies. Maybe there are lessons here for you and your doctors, especially about the under-utilized HD IL2.
Clinical benefit (CB) of high-dose interleukin-2 (HD IL-2) in clear cell (cc) metastatic renal cell carcinoma (mRCC).
(Abstract is below)
There are few new studies about the use of HD IL2 following the approval of the targeted therapies. The ease of use of these agents, along with the desire not to send patients to specialty centers for IL2, limited its use. It was difficult to select patients, and the CR and PRs were relatively small in number. Doctors often did not discuss the possibility of a cure with their patients. Did patients also miss the chance for Stable Disease, and with it, a “Clinical Benefit”?
Patients in this study who did not have a CR, but whose cancer stopped growing benefited. That CB was not counted in terms of the approval of the drug, nor do doctors consider it in their recommendations. Should this possibility be discussed with patients? Most patients would surely answer, “Yes!” to that question.
The researchers recognize of the value of Stable Disease (SD) as an outcome, versus only Complete Response (CR) or Partial Response (PR). The usual outcome measures, Progressive Free Survival (PFS), or Overall Survival (OS), are noted, as isTime to Next Treatment (TNT). TNT implicitly recognizes that a failed or limited response will likely be followed by another treatment. Early on, there were no subsequent treatments, sad to say.
The original clinical trial which led to FDA approval of HD IL2 recognized only CR, which was 5%, with the median not reached during the trial, and PR, which was 14%. Study footnotes indicate that three of the PRs had surgery which rendered them disease free at the time of the publication. This would now be called a “salvage therapy”, and put them in the No Evidence of Disease (NED) class. A different analysis of this data would have upped the CRs some small percentage, and some SD would also have been found.
Also the definition of PR was 50% or greater reduction in measurable tumor size, the sum of the perpendicular diameters of all lesions, with no new increase of size of any other mets. Far less strict measurements of PR were used in the targeted therapy trials, with a 30% tumor reduction defined as a Partial Response.
With those definitions in mind, note that there are CRs in 11% of patients, with a PR in an additional 6% of patients. Most important is the SD category, which was achieved for 31% of all patients. This total of 47% is described for the group as being of Clinical Benefit (CB). Certainly patients value the responses of SD, which seems to have provided slightly over one year versus 3-4 months benefit to those who did not have SD.
When comparing the value of Objective Response (OR) with its median of 1616 days to that of Stable Disease (SD) measured as 1476 days, one can clearly see the value of achieving Stable Disease. Unfortunately, those patients with Progressive Disease, or with responses Not Evaluable (NE), showed OS of 365 days.
Patients should be aware of these definitions and the impact the lack of parallel comparisons in making these critical decisions. Ten years ago, the patients reminded one another to stay alive until the next treatment. Having Stable Disease made that possible. Let’s apply the same tests to all the available treatments when making these life-changing choices of treatment.
ABSTRACT FOLLOWS Citation: J Clin Oncol 32, 2014 (suppl 4; abstr 461)
Author(s): Neeraj Agarwal, David D. Stenehjem et al University of Utah, Huntsman Cancer Institute, Salt Lake City, UT; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; Pharmacotherapy Outcomes Research Center, College of Pharmacy, University of Utah, Salt Lake City, UT
Background: HD IL-2, an immunotherapy, is a standard of care for a select group of patients (pts) with mRCC. Generally objective response (OR) rates, i.e. complete response (CR) + partial response (PR), of 16-20% are discussed with pts, but not disease stabilization (SD). Recent data suggest that cancer immunotherapy may improve survival without inducing OR. Thus, treatment with HD IL-2 may provide survival benefit to an additional group of pts not experiencing OR, but only SD as the best response. Here we report CB (OR+SD), and specifically report outcomes of cc mRCC pts experiencing SD as the best response, on treatment with HD IL-2.
Methods: All sequential cc mRCC pts treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000-2012 were included. Pts were evaluated for best response, progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS). Two practitioners independently reviewed HD IL-2 response with discrepancies adjudicated by a third reviewer.
Results: 85 pts, 79% male, were identified with a median age of 56 (range 32-76) years. Pts belonged to the following MSKCC risk categories: 11 (13%) good, 70 (82%) intermediate, and 4 (5%) poor risk. A CR was identified in 9 (11%), PR in 5 (6%), SD in 26 (31%), progressive disease (PD) in 38 (45%), and unknown/not evaluable (NE) in 7 (8%) pts; yielding a clinical benefit in 40 (47%) pts. The median PFS, TNT, and OS in these individual groups of pts are compared in the table.
Conclusions: A clinical benefit of HD IL-2 was achieved in nearly half of all clear cell mRCC patients. OS was not significantly different in OR and SD groups. Even though OR favorably determine outcomes, SD is also an important response criterion, and may be discussed during counseling patients for treatment with HD IL-2.
|PFS, days||TNT, days||OS, days|
|SD vs PD and NE||337 vs 78 (p<.0001)||373 vs 110 (p=.0001)||1,476 vs 365 (p=.0003)|
|CB vs PD and NE||791 vs 78 (p<.0001)||735 vs 110 (p<.0001)||1,616 vs 365 (p<.0001)|
|OR vs SD, PD and NE||NA vs 99 (p=.0003)||953 vs 166 (p<.0001)||1,616 vs 603 (p=.0021)|
|OR vs SD||NA vs 337 (p=.0234)||953 vs 373 (p=.0015)||1,616 vs 1,476 (p=.2094)|
|Abbreviation:PFS, Progression Free Survival; TNT, Time to Next Treatment, OS, Overall Survival; NA, not achieved;SD, Stable Disease; PD, Progressive Disease; NE, Not Evaluable; CB, Clinical Benefit;CR, Complete Response; PR, Partial Response;OR, Objective Response|
Abbreviation: NA, not achieved.