DR LOVE: Just to clarify, what was your impression of what was causing the pain?

DR SCHER: It wasn’t clear to me. The MRI revealed abnormalities in the C-2 vertebral body, but they didn’t appear large enough to cause pain. No pressure was exerted on any of the nerves. His orthopedic surgeon was convinced that his pain was not related to adenopathy. He felt it was restricted to his left shoulder and a result of playing golf. Over the subsequent week or two, his pain was somewhat alleviated without treatment. We weren’t convinced that the pain was definitely related to his lymphoma, but I was concerned.

DR HAINSWORTH: Was the C-2 lesion another sclerotic area or was this a lytic lesion on plain films?

DR SCHER: We don’t have plain films, just the PET scan. The MRI just showed an abnormal C-2. I did not actually see the scan, but I think it was probably more sclerotic. I don’t think any evidence indicated it was lytic.

DR GOLDBERG: With the vertebral lesions, is anyone thinking about using radiation therapy in a localized manner?

DR HAINSWORTH: I think that would be a reasonable option. If I were starting with systemic treatment, particularly first-line treatment, I probably would not do that. I don’t believe these lesions are presently at high risk of having collapse or pathologic fracture, if, indeed, they are both sclerotic. If this were a patient for whom systemic treatment was not an option, I would consider radiation therapy.

DR RADER: My understanding is that SUV values are not standard across the spectrum by various PET scan techniques and PET scanners. Relying on one value may be OK in one institution, but do those numbers apply across various institutions?

DR CABANILLAS: Some nuclear medicine physicians are not sold on the idea of the SUV, but the data are beginning to accumulate — not only in lymphoma, but in other tumors like breast cancer, in which a correlation exists between the histologic grade and the degree of SUV uptake.

In dealing with nodal sites of biopsy, how do you feel about making a diagnosis with needle biopsy and flow cytometry, especially with transformation, versus evaluating a whole node? Do you think the science of molecular biology has changed enough that we could make a diagnosis based on a small needle biopsy of lymphoma? In the past, a single biopsy was inadequate and we always demanded a full node.

I don’t like to do an FNA for the primary diagnosis, but in a patient who already has an established diagnosis for whom I am trying to establish transformation — with a good cytologist — I rely on the FNA.

I prefer to do a lymph node biopsy, if possible. That’s easy to do when you have peripheral adenopathy, but if you have a bony lesion, for example, then your option is to either do an open biopsy or a needle biopsy.

If you ask the pathologist for evidence as to whether the tumor is transformed, rather than asking exactly what kind of tumor it is, you’re more likely to get the right answer. An evaluation of Ki-67 can give you an idea about the proliferative rate. We have accumulated evidence regarding the correlation between Ki-67 and histologic grade, and a correlation definitely exists. I tend to rely on FNAs only when performed by a good pathologist or cytologist who has a lot of experience with lymphoma cytology. I never recommend an FNA for the primary diagnosis, only to establish a relapse and transformation.

DR BHARDWAJ: We are seeing the difference in terms of how the two faculty members would handle this patient if they decided to treat. There is the RFND school, and the other school of CVP or CHOP with rituximab. What data exist in terms of favoring one over the other and how meaningful is a molecular remission in terms of either survival or quality of life?

DR HAINSWORTH: I think we agree that the data isn’t as complete as we’d like for it to be. In the pre-rituximab days, the fludarabine- based regimens were somewhat better than the alkylator-based regimens in low grade lymphoma, at least in some parameters. The data from two large randomized trials showed that complete response rate, molecular complete response rate and progression-free survival were consistently higher with fludarabine-based regimens.

What happens when you add rituximab to the mix is not clear. Certainly, in both areas, the molecular CR goes up. It will probably continue to be higher in the fludarabine combinations plus rituximab than with the alkylator combinations plus rituximab. No head-to-head comparison has been done, so it is difficult to know which chemotherapy to use with rituximab.

If you evaluate the two randomized trials that utilized straight chemotherapy with or without rituximab — which were CVP and CHOP — CHOP appears to be more active than the CVP; however, we already knew that, at least as far as initial activity and CR rate. Does that translate into a better regimen? I think the meaning of a molecular CR in low grade lymphoma is still debated. Molecular CR clearly leads to a longer remission. Does that lead to longer survival? I think we’re becoming more optimistic about that, but it has not yet been proven.

DR BHARDWAJ: Does exposure to fludarabine early on in the treatment course interfere with options down the road?

DR HAINSWORTH: I think it does in some patients, but in general, the answer to that question is no. Whatever you use as initial chemotherapy interferes down the road, and patients have more bone marrow problems as you progress from first- to second- to third- to fourth-line regimen.

DR LOVE: Fernando, it seems that in this situation, the base of the therapy is the rituximab. How much benefit does chemotherapy add? What clinical trial evidence do we have, particularly in terms of survival, regarding the impact of adding chemotherapy in addition to rituximab in this situation?

DR CABANILLAS: Rituximab is a relatively new agent, so we don’t have 10-year follow-up data. All we have is relatively short follow-up, perhaps not even five years, and we have molecular remission data that are associated with a longer failure-free survival. We are projecting what’s going to happen in the future based on that. A lot of people are using R-CHOP based on the small series that was published by Myron Czuczman from Roswell Park.

Even though the data look intriguing with very good response rates, durations and even molecular remissions, the followup is not long enough and the number of patients is small. I think the larger experience is with the FND/rituximab, where more patients have been systematically staged and treated. Czuczman’s data covers multiple stages, including Stage IV and earlier stages. The FND/rituximab data is purely Stage IV.

DR MALHOTRA: Fernando, what is your experience with fludurabine-based regimens in terms of immunosuppression, especially in an asymptomatic patient like this one? What do you tell them? Our practice recently almost lost two patients who had pneumocystis pneumonia. We never had that problem with CVP-based regimens.

DR CABANILLAS: That’s definitely a risk, which we identified early on in the FND trial. The first FND trial was done as a salvage regimen, and we observed a couple of cases of pneumocystic carinii pneumonia, so we started using sulfamethoxazole and trimethoprim (Bactrim^®) prophylaxis during the weekends. We instructed the patients to take one double-strength Bactrim twice a day on Saturdays and Sundays. They do that while they’re on treatment and continue for at least three months after they finish the treatment. Since we began doing that, we haven’t seen any more pneumocystis.

Now my concern is the cases of hypogammaglobulin anemia that frequently occur. If a patient is receiving a combination of chemotherapy and rituximab, and develops recurrent sinusitis that responds to antibiotics but reoccurs upon cessation of antibiotics, you can bet that the patient is most likely hypogammaglobulinemic. You can treat the patient with gammaglobulin, which will usually cure the problem for several months to a year.

We have also seen patients who have developed a parvovirus infection with marrow aplasia. Again, those cases are patients who develop hypogammaglobulin anemia, so if you give them gammaglobulin, their bone marrow will recover; however, fludarabine has a cumulative toxicity in the bone marrow independent of parvovirus, so you have to be careful to not overtreat.

It’s important to stop fludarabine at the first signs of thrombocytopenia; don’t wait until the patient becomes severely thrombocytopenic. If a patient develops 90,000 platelets, and they take six to eight weeks to recover, the bone marrow is already intoxicated with fludarabine. If you keep pushing, you’re going to run into trouble. You have to strike a balance when you use this kind of regimen, especially in elderly patients.

DR C FARBER: I would like to reiterate two points that our faculty touched on. First, Dr Hainsworth mentioned that he was concerned about the location of the tumor. If you have a lymph node that grows over a period of a few months, it’s not a big deal; however, a C-2 lesion could cause spinal cord compression. I think that’s critical.

Second, Dr Cabanillas mentioned that it might be worth performing a fine needle aspiration (FNA). That is a relatively inexpensive, low-tech way to evaluate a tumor, and it gives you a definitive answer. If you see transformed cells, it changes your management of this patient. You would go with R-CHOP or something more aggressive.

I think the location and the unusual nature of the tumor begs to determine exactly what you’re dealing with.

DR KAPLAN: Can I ask you about fludarabine in the elderly? I had a startling conversation with some folks from Memorial Sloan- Kettering, and they don’t use fludarabine in patients older than 70 years of age. How do you feel about that?

DR CABANILLAS: In our trial, age 75 was the cutoff. So, we have treated patients up to age 75.

DR KAPLAN: We’ve used it in much older patients without much trouble; however, we don’t use as much as in many of the clinical trials. We use it for three days in a row and usually give four cycles instead of six, and we rarely run into trouble.

DR CABANILLAS: Your point is well taken. The FND combination is three days of fludarabine, not five days, like with the single agent. That’s one of the reasons it’s relatively well tolerated.

I think time will tell you how the patient tolerates it. The toxicity is not only acute, but also cumulative, so if you start seeing cumulative toxicity, you know that the patient is heading for trouble.

DR LOVE: I would like to hear about the discussions you have with patients with asymptomatic indolent lymphoma. How do you approach decision-making in that situation, Dr Farber?

DR C FARBER: I don’t know if any area of oncology is more complicated than managing low grade lymphomas. It’s almost counterintuitive. You sit down with a patient who often is surprised at the diagnosis. “How could this be? I’ve been healthy my whole life. I’ve felt that lymph node for months.”

The patients have a tough time understanding, and that is appropriate because it’s often not curable. Of course, we need more follow-up on the issue of rituximab, but no definitive evidence indicates that early intervention translates to an improved outcome — people living longer or with a better quality of life.

For many people, observation without treatment is counterintuitive. I tell my patients it’s akin to being in a war. You know at some point the battles are going to start, but they haven’t started yet so there’s no need to be shooting off your ammunition. This is a difficult concept for some patients, who say, “The treatment is there. Let’s put me in remission.”

They have a tough time with the concept of waiting for something to happen because they want to be more proactive. Some people loathe the idea of chemotherapy and would postpone it at all costs. For other people, the concept of just waiting is extremely difficult.

DR RADER: The one thing that’s made a difference in the management of these patients is rituximab. I loathed treating lymphomas in the old days. I don’t believe any good survival data exist, no matter what treatment you use. We have disease-free survival data but no overall survival data. Rituximab makes it easier because you have some patients who are borderline whom you want to treat.

DR CABANILLAS: In low grade lymphoma, the basis for the watch-and-wait approach is that the disease is considered incurable. First, we need to clarify that the lack of curability holds mostly for Stage IV presentations, which are the majority of cases. Second, the other rationale is that if you cannot cure the disease and you don’t need to palliate anything because the patient is asymptomatic, why treat early?

I’m going to say something controversial and no one is going to believe it, but data from the various studies we did over the last 25 years at MD Anderson indicate a plateau in the curve, and that plateau has been increasing through the years as we modified the regimens.

The plateau occurs at approximately eight years, and at 15 years, 40 percent of the patients are alive without evidence of disease. I think people have not realized that there is a plateau, mostly because they’ve been using single agents or palliative types of therapy, but also because they haven’t followed the patients long enough. If you stop your observation period at five to 10 years, you fail to see that the tail end of the curve plateaus — just as in large cell lymphomas.

I believe that if you treat Stage IV low grade lymphoma appropriately, you can cure a fraction of the patients — not necessarily the majority — but more or less about the same that you cure with large cell lymphoma.

Sandy Horning has a slide she shows that indicates that the survival of low grade lymphoma has not changed for 20 years, which is true at Stanford. But they’ve been doing the same thing, over and over again. Why would you expect to see a change? We’ve been changing the regimens every four to five years, when I evaluated our data. I was surprised that we are now seeing a definite plateau in the curve.

DR LOVE: John, agree, disagree, or in between?

DR HAINSWORTH: First, I think his statement that this would be controversial, is true. I believe that these patients have been overtreated with combination chemotherapy for years. I know I’m sounding like a nihilist, which I’m not. We have data from many years of treatment with standard combination regimens of various types, and I’m not sure anybody has, in any controlled way, shown any plateaus on the curves. I would love for that to be true, but I’m not convinced of it yet.

DR CABANILLAS: I would like to respond to that because you said precisely the right word, “standard” therapy. It became evident that when we began to try new things, such as adding interferon, that gave us a better survival and disease-free survival. Then we began alternating regimens, and now, with FND, the plateau in the curve appears better and better.

DR LOVE: What’s the number in the rituximab era? Do you have that data at this point?

DR CABANILLAS: The rituximab trials don’t have as long of a follow-up, but we have 90 percent of the patients alive at five years. With the simultaneous approach using FND/rituximab, the failure-free survival was around 60 percent at five years. Obviously, that is going to change, because the plateau doesn’t seem to occur as early with low grade lymphoma as with large cell lymphoma. It takes approximately eight years.

DR L FARBER: If you have the opportunity to observe these patients to evaluate the pace of the disease over time, you’ll have a much better feel than if you’re asked to make a decision at one point in time. We all have to listen and respond to the patient, and many patients will not accept a watch-and- wait approach no matter how persuasive we try to be.

We might be able to convince them to try it for a week or two, but they come to us because they want us to do something for them now. Where I live, few patients seek second consultations and opinions, so it’s a little easier. I’m a therapeutically oriented oncologist and I’ve always had difficulty watching and waiting. The era of rituximab makes it a lot easier to not watch and wait.

Nonetheless, I think that we have to listen to our patients. Some patients are going to accept the concept of watching and waiting, while other patients are going to say, “This is just not for me. I am not sleeping at night because I can’t stand to live with this cancer.” It requires a tremendous amount of persuasion and I think rituximab offers us somewhat of an out — maybe not an easy out, but an out nonetheless.

DR C FARBER: Those patients call it “watch and worry.”

DR LOVE: Dr Farber, how do you approach the issue of whether to utilize chemotherapy in addition to rituximab? It reminds me a little bit of the breast cancer situation with trastuzumab. Are you going to use trastuzumab alone in metastatic disease or add in chemotherapy? Research leaders in breast cancer often start with trastuzumab alone and then add in chemotherapy if the patient is not doing well. Is that an approach you utilize in NHL as it relates to rituximab?

DR C FARBER: I agree with that. For the patient who really needs some form of treatment, you don’t want to do any harm. Fludarabine, given long term, causes immunosuppression and myelosuppression. Rituximab is a good agent to start with, and it offers the patient real response rates.

I think a relatively low morbidity occurs with rituximab, and it can be used repeatedly. In many ways, it’s a good agent for use in those patients because they feel more proactive.

Previous page | Select publications
Page 2 of 2