Intuitively, you'd think that people who are doing worse while getting treated for lung cancer are not going to do as well as people who have improvement in their symptoms after treatment starts. But how much do patient symptoms count in our current medical system for deciding whether a treatment is working or not, and when to move to a new therapy? The answer is that patient reported symptoms don't have a clear role yet. That has partly been because developing and using validated, predictive symptom scales can be expensive and challenging to get full participation, these scales haven't been clearly correlated with more established efficacy measures like response rate on CT scans and overal survival, and it hasn't been clear whether the FDA would accept such measures in appoving a new drug. A drug that is shown to improve survival is highly likely to be approved, since most doctors and many patients consider how much a treatment improves survival to be the most important benefit a cancer treatment can deliver. And unlike many symptoms that can be subject to a placebo effect and can only be assessed by the patient, survival is a "hard endpoint" that isn't really subject to any debate. But obviously survival is only one aspect of the treatment experience, and it's not something you can get early feedback on.

But there's a growing momentum for incorporating patient feedback as an early indicator of the value of a treatment. I'll write a few posts in the coming days and weeks about the challenges nd developments of patient-reported symptoms and quality of life assessment in oncology. In the meantime, I'll start with a report that demonstrates that patient symptoms are correlated with our conventional measures of efficacy.

Filippo de Marinis and colleagues did a retrospective review (abstract here) of an important phase III trial in advanced NSCLC that I've described in a prior post, directly comparing taxotere to alimta as a second line treatment. To summarize that trial in one sentence, it showed that alimta and taxotere had essentially identical activity, as well as quality of life, but a few of the blood-related side effects were significantly less with alimta; this led to the FDA approval for alimta as a second-line treatment for advanced NSCLC. Of note, in this trial, as well as all of the other large trials of second or third line treatment, the response rates are very low, in the 6-10% range, despite the apparent benefits in terms of improved survival from these agents for a broader population.

The current analysis looked at a symptom assessment that entailed patients marking a spot along a 100 mm/10 cm line (marked from 0 to 10 at each 1 cm interval) to rate their level of perceived severity of several lung cancer-related symptoms (loss of appetite, fatigue, cough, shortness of breath, coughing blood (also known as hemoptysis), and pain), as well as more global scales for overall symptom distress, activity level, and health-related quality of life. Patients completed these forms before starting treatment and then weekly, at the end of treatment, and they also tried to get patients to continue to do these assessments after they came off the trial if they hadn't started a new treatment.

What will probably surpise nobody but is worth actually showing is that the people who responded also experienced an improvement in their symptoms, except for coughing up blood, that wasn't seen among people who didn't respond. However, as we've also seen with stable disease and survival (a trend where outcomes among those with stable disease is a little better but not as favorable as among objective responders), the nearly 50% of people who achieved stable disease also had a modest improvement in symptoms (upward bars mean symptom improvement, and downward bars mean symptoms worsening):

On the other hand, patients with symptom worsening had an overall trend toward a slight decline in symptoms.

In addition, while the overall trend was toward an eventual worsening of these symptoms over time, even among people who responded, the time to symptom worsening was correlated with progression-free survival and also overall survival in the trial, again for every symptom except for coughing up blood. I'd imagine that the correlation with hemoptysis was not seen because only a minority of patients will experience this, even as a cancer progresses, since this would presumably occur only when the cancer is growing near and eroding into a blood vessel large enough to cause this symptom.

This isn't the first trial to include assessment of patient symptoms along with CT scans and follow-up for survival. This is part of a growing trend, which has the advantage of both recognizing the role for patient experience as an important endpoint in itself, and in evaluating whether patient experience can provide early feedback about the utility of a particular treatment when there are many potential choices. It also highlights that patients achieving stable disease overall can obtain benefit from treatment, that benefit is not restricted to the small minority of patients who achieve a major tumor shrinkage of 50% of more.

I'm going to review some more work on the benefits and limitations of patient-reported outcomes. I expect that the patient experience will play an increasing role in assessing the benefits of a cancer treatment, both to oncologists and to the FDA. More later.