Falling Short

When a new cancer treatment is being tested, patients are closely followed in clinical trials. This way, researchers can determine the optimal dose, which is one that offers the least amount of side effects and the best shot at survival. But once people start getting that treatment outside the sheltered setting of a study, doctors often make adjustments and it's not always known if the treatment being delivered matches the treatment the trials found most effective. The difference might ultimately affect the how well people do after receiving these potentially life-saving treatments.

That's why Gary H. Lyman, MD, a professor of medicine and oncology at the University of Rochester in New York, and colleagues decided to look at records of more than 4,500 people with an aggressive form of non-Hodgkin's lymphoma. The researchers wanted to see if the patients were getting chemotherapy at the doses and on the schedule that is recommended by the trial, and if not, why not.

Last year, Dr. Lyman and his colleagues reported on a breast cancer study that found more than half of women getting chemotherapy after right after surgery were being under-treated. "We were shocked with the results in breast cancer, so we decided we would also look at another curable type of cancer, aggressive non-Hodgkin's lymphoma, because we know from the randomized, controlled trials that patients who are treated appropriately have a good chance of long-term survival and possible cure," Dr. Lyman says.

In the non-Hodgkin's lymphoma study, which was published in September in the online version of the Journal of Clinical Oncology, the researchers reported that about half of the patients, particularly older people, were under-treated, and that many of them were not getting the appropriate supportive therapy for their treatment side effects.

"There's enormous variability in how aggressively patients are supported and how well treatment guidelines are followed around the country," Dr. Lyman says. Below, Dr. Lyman discusses his findings and how to ensure that more patients with non-Hodgkin's lymphoma get the right treatment, so that they have the best possible chance of being cured.

What is non-Hodgkin's lymphoma?
Non-Hodgkin's lymphoma is one of the most common types of lymphoma; lymphomas are cancers of the lymph glands and nodes that can occur virtually anywhere in the body. While Hodgkin's disease can often occur in younger patients, non-Hodgkin's disease occurs in a somewhat older population, around age 60, but it can occur almost at any age. We don't know all the reasons for this, but it is one of the cancers that has increased in incidence over the last two or three decades and now affects approximately 50,000 individuals throughout the United States each year.

Its aggressive form is, fortunately, a very responsive and potentially curable cancer, like Hodgkin's disease. Anywhere from a third to a half of patients are cured and can go on to live a normal lifespan, if they're treated appropriately.

So in non-Hodgkin's lymphoma, aggressive disease is more responsive to treatment?
Yes, this is kind of a paradox that we see with many rapidly growing cancers. The cells that are more rapidly dividing tend to be more responsive because many of the chemotherapy drugs are most active against rapidly growing cells.

How is non-Hodgkin's lymphoma treated?
Some patients with very early stage disease may get a shorter course of chemotherapy combined with radiation therapy to the affected area. But, in the vast majority of patients, the cancer needs to be treated systemically with chemotherapy because the cells may be anywhere in the body. The usual chemotherapy regimen is a combination of four or five drugs given every three weeks for six to eight treatments. So the whole treatment program can run over a period of about four to five months.

Are people with non-Hodgkin's lymphoma being under-treated?
We were shocked at the magnitude of the under-treatment that we observed. Approximately half of patients with this potentially curable cancer receive substantial dose reductions or treatment delays during their course of chemotherapy. While we don't have long-term follow-up on these patients, we know from clinical trials that patients who receive the full treatment do better than patients whose treatment is substantially compromised. So our real concern here is that their chances of long-term survival and cure are being seriously compromised by the way the treatments are being given.

Which patients were most likely to receive lower doses or have delayed care?
We found that older patients are more likely to be under-treated. We also found that patients with a higher stage of disease, patients who were less able to care for themselves and function normally, and patients with poorer nutrition were more likely to have dose reductions and treatment delays.

Which patients were more likely to receive the appropriate treatment?
There were two factors that were significantly associated with better treatment intensity. One was just timing. We've seen some slow but consistent improvement over the six years of study, so that patients treated more recently had fewer dose reductions and treatment delays, down more in the 40 percent range, compared to those back in the mid-90s, where it was closer to 60 percent.

The other was that patients who receive preventative care, specifically treatment to boost low white blood cell counts caused by chemotherapy, are more likely to receive the dose on time and to receive fuller dose intensity than those patients who didn't receive these agents. Unfortunately, only about 12 percent of the entire population received these medications from the beginning, for various reasons.

Do you think that patients are not getting appropriate treatment because of concerns about side effects?
I have no doubt that that's part of it. We actually broke reductions in dose intensity into two components. One category was reductions that were planned from the very beginning, before the patient had received any treatment. In those cases, there seems to be a conscious decision on the part of the treating physician that the patient won't tolerate the chemotherapy well.

Then there are reductions that occur subsequent to starting therapy, which are usually a result of side effects from the treatment. One of the strategies to reduce the side effects of treatment is to cut back on the strength of the medication. Unfortunately, that probably raises the potential that those patients will have their disease come back months or years later.

How can we make sure more people receive the appropriate treatment?
There probably are some patients where reductions are completely unavoidable. Our estimate is that that's in the range of 5 to 10 percent. It's certainly not in the range of 50 percent of patients.

Older patients, and patients who have more symptoms from their disease or a higher stage of disease, do need more aggressive supportive care. But if they are supported and then treated the same as younger patients are, they are just as likely to be cured of the disease. Identifying the risk factors, such as age, that either lead to more side effects or lead the oncologist to reduce the doses or schedule of the treatment before treatment, can help us target the available supportive care towards those patients at higher risk, hopefully, to enable them to receive the full program.

What does supportive care involve?
Supportive care has improved tremendously over the past decade. We do a much better job than we used to in terms of controlling nausea and vomiting, for example. The most common toxicity that we observed in this study population that lead to dose reduction was low white blood cell count, which will occasionally result in an infection. But we have treatments that can improve the blood counts and reduce the risk of infection. Rather than cut back on the strength of the program and compromise someone's future, we should really pull out the necessary supportive care to allow them to go through the full program.

What advice do you have for recently diagnosed non-Hodgkin's lymphoma patients?
My main advice is to become knowledgeable about your disease and to ask what kinds of treatments are available. Ask the oncologist about the side effects of those treatments and what will be done to alleviate or prevent them.

I deal with patients day-in, day-out in my own practice, and I know they are coming in increasingly aware of the importance of getting the full treatment program. If I suggest cutting back on the strength as one option to alleviate side effects, that is almost universally rejected by the patients because they fear the cancer more than they do the side effects. So, I think the oncologist and the patient really need to talk about minimizing side effects and optimizing the treatment.

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