From the GRACE Archives -- Originally Published November 5, 2009 | By Dr. Weiss
I treat cancer for two and only two reasons. I want my patients to live longer and with a higher quality of life. All other measures are surrogates, and that includes cancer growth or shrinkage. For years, oncologists focused on survival as the primary outcome of trials. We assumed that any therapy that could knock down cancer would also make patients feel better. In fairness to the older trials, this assumption often was right. When cancer grows, it can cause such terrible symptoms that even a therapy with bad side effects can lead to a better quality of life than if the cancer was left untreated. However, as our drugs have improved, we have become pickier and now demand that new drugs not only knock down cancer better, but also have fewer side effects. Most new trials incorporate robust measures of both side effects and quality of life. Some trials even seek improvements in quality of life as their primary endpoint.
Every patient has different priorities and values, but I keep hearing the theme of “quality over quantity” from a sizable portion of my incurable patients. I think that most of my colleagues, including trialists, now acknowledge the importance of quality of life in palliative therapy. However, this recognition has lagged in potentially curable disease, whether the cure is attempted via chemoradiation or surgery plus adjuvant chemotherapy. With this issue in mind, two recent trials in the Journal of Clinical Oncology (JCO) are heartening.
The first study is derived from RTOG 9801. This trial randomized patients receiving chemoradiotheray with curative intention to receive amifostine or placebo. The goal of the trial was for amifostine to decrease the toxicity of radiation. Unfortunately, the trial was negative, with no difference between the amifostine or placebo group in survival, toxicity, or any other measure. However, the trial did teach us an unexpected but very important lesson.
Since the trial was negative, the amifostine and placebo groups are equivalent and all patients in the trial can be evaluated for other prognostic factors without regard to assignment to receive amifostine or placebo. When this is done, the most important prognostic factor predicting for survival is patient-reported quality of life at the beginning of the trial. The yellow curve below represents patients with an above average quality of life at study initiation and the blue curve patients with below average quality of life. You could drive a Mack truck between the survival curves with the yellow curve representing survival of patients with a score above the median, and the blue curve representing patients with a less than average score.
The quality of life score was so predictive of survival that even Karnofsky Performance Status, a classic practitioner-measured instrument for performance status, fell out as a prognostic factor in a model for overall survival. The implications of this finding are not just philosophical, they are also practical. In trials, we often stratify patients by variables that we think are important for survival. For example, if a trial allows patients with varying performance status, we make sure that an equal number of patients with poor or great performance status are assigned to each of the two arms of the study. In this way, any differences between the groups can be attributed to the intervention (usually a drug) and not to chance imbalances in some important factor. These results suggest that we can make better trials by stratifying by patient-reported measures of quality of life than by practitioner-measured performance status.
The second trial involves an impressive use of complex mathematics to prove an incredibly human point: that adjuvant chemotherapy after surgery improves quality of life. At a time when we did not yet know that chemotherapy added to survival, the JBR.10 study randomized patients to either chemotherapy or observation alone after surgery. Patients who had stage IB or stage II disease were randomized to receive cisplatin and vinorelbine (in my opinion, the first of the “modern” regimens) or observation. Overall, the study showed a 15% improvement in absolute survival at 5 years with patients living an average of 73 months without chemotherapy and 94 months with it.
However, these results left many doctors and patients wondering: is 15% worth the toxicity of therapy? Our Candadian colleagues took a stab at this question using a measure called Q-TWiST, which originally was used to evaluate adjuvant chemotherapy in breast cancer. Q-TWiST stands for quality-adjusted time without symptoms and toxicity. To get to Q-TWiST, you start with TWiST. TWiST subtracts “time with toxicity” from “disease-free survival” (time alive and without cancer) to get the amount of time that the patient was alive, cancer-free, and feeling well. Q-TWiST then adjusts this score based on the relative values that a patient places on each of these states. Ideally, these valuations would come from the patients themselves. Since the authors did not ask them, they instead derived them from various (reasonable) sources. No matter how they calculated it, chemo came out on top.
In order to make chemo lose, the patient would have to value time with toxicity less than half that of time without symptoms. The authors summarize their findings well, “as long as living with chemotherapy-related adverse effects, such as fatigue, nausea, and vomiting seen in the JBR.10 is worth half as much as being healthy, then chemotherapy will pay off.”
Both of these trials should arm your oncologist to have a better conversation with you about quality of life in the context of curative-intention therapy. Both suggest routes to better clinical trials. Intelligent discussion of both requires some pretty heavy statistical terms. I have spent time looking at GRACE posts from the past few months, and I am impressed by the descriptions of really complex cancer findings in fairly simple English. Dr. West posted a great article on cancer trials terminology in 2007 to which I refer the confused. I am also considering posts on the following topics:
- *How do researchers get ideas for trials
*Clinical trial vetting process and pt safety protection
*What are the different kinds of trials
*Why you should consider trials (in case it doesn’t shine through I’m a huge trials believer)
*Trials open nationwide
*How to “trial shop”
Since this site is here to serve you, please let us know what topics would be most helpful!