1. Carlson, Robert H.

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Patients with stage I follicular lymphoma who are rigorously staged have a high survival rate regardless of the type of treatment they receive, including watchful waiting, according to a new analysis from the National LymphoCare Study (JCO 2012;30:3368-3375).

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And outcomes were good whether or not patients received radiation therapy: Those receiving either rituximab-based chemotherapy or systemic therapy plus radiation had significantly increased progression-free survival at five years compared with patients receiving radiation therapy alone.


The authors say the data question whether radiation therapy, the historical standard and the modality in the National Comprehensive Cancer Network (NCCN) guidelines as the preferred treatment for Stage I follicular lymphoma, is in fact the best choice.


While the registry study's authors acknowledge that it is limited in terms of providing definitive therapy recommendations, they said the data do "challenge the paradigm that XRT should be standard for this presentation."


As the first author, Jonathan W. Friedberg MD, MMSc Professor of Medicine and Oncology and Chief of Hematology/Oncology at James P. Wilmot Cancer Center, said in an interview, "My interpretation of these results is not to compare modalities because the numbers are too small, but there are a number of different approaches that can be utilized, and there are select patients where observation is a very viable option. And in an era of cost containment, this type of comparative effect analysis is going to become increasingly important in how we make treatment decisions."


The National LymphoCare Study-the first report of which was published in 2009 (JCO 2009;10:1202-1208)-is a disease-specific, prospective observational study, sponsored by Genentech and Biogen Idec, that enrolled approximately 2,700 patients with newly diagnosed follicular lymphoma from 2004 to 2007.


In the analysis of rigorously treated patients, at 57 months, there was one progression-free survival event among 26 patients (4%) receiving combined modality with radiation; nine among the 57 patients (16%) receiving rituximab-chemotherapy; six among the 25 patients (24%) receiving rituximab monotherapy; nine among the 35 patients (26%) under watchful waiting; and 18 among the 56 patients (32%) receiving radiation therapy alone.


Should Encourage Patient Discussion

Friedberg said the literature that led to the NCCN guidelines for Stage I disease is based mostly on single-institution retrospective studies from the pre-rituximab era, while the new study includes patients treated with rituximab.


He allowed that a registry study is inadequate for most types of evaluation, "but given the relative rarity of the presentation, as well as the good outcome of the patients, the fact that we have five years of follow-up in 206 patients is a very meaningful contribution," he said.


The data should give the NCCN guideline writers something to reflect on, he said.


"In my practice, this data set has suggested that although radiation therapy remains a very good option, there are other treatment approaches that result in similarly good outcome. This should encourage physicians to have discussions with their patients abut the risks and benefits of certain therapies in an individual situation."


The risks from radiation therapy vary, Friedberg continued: In a patient with a single cervical node the risk might be quite low, while if the disease is in the abdomen, the risk of acute morbidity could be higher. "In the past, we struggled with the fact that we would push radiation therapy even to some of these areas where there might be more risk because it provided the 'best' outcome. In my mind, this study calls that type of behavior into question, and suggests there might be multiple ways to achieve excellent outcomes-including no treatment at all."


Rigorous Staging

Of the 471 patients identified in the registry as having Stage I follicular lymphoma, 206 underwent rigorous staging, defined as bone marrow biopsy, computed tomography imaging, and/or FDG-PET scanning.


The analysis showed that rigorously staged patients had superior progression-free survival rates compared with non-rigorously staged patients, with a hazard ratio of 0.63.

JONATHAN W. FRIEDBER... - Click to enlarge in new windowJONATHAN W. FRIEDBERG, MD, MMSC: "In my practice, this data set has suggested that although radiation therapy remains a very good option, there are other treatment approaches that result in similarly good outcome. This should encourage physicians to have discussions with their patients about the risks and benefits of certain therapies in an individual situation."

Friedberg said most patients in the nonrigorous category were there because they did not have a bone marrow biopsy, which could be for several reasons. "If you have an elderly patient you may not want to put them through a bone marrow biopsy."


The study found that 64 percent of patients older than age 60 were non-rigorously staged, vs. 52 percent who were. "Or some people may say that if they're going to observe the patient anyway it doesn't matter whether the patient has early or advanced stage disease, or some might feel that if they're going to treat with R-chemo anyway, it doesn't really matter if there is some asymptomatic disease in the bone marrow."


But Friedberg said he felt that an accurate prognosis is not possible without rigorously staging. "If you want to use this data set to say there are numerous approaches to manage a patient with Stage I, you better make sure they have Stage I disease."


NCCN Reaction

A member of the NCCN follicular-lymphoma guidelines panel said the organization stands by its recommendations. Richard T. Hoppe, MD, the Henry S. Kaplan-Harry Lebeson Professor in the Department of Radiation Oncology at Stanford Cancer Institute and a member of OT's Editorial Board, said the LymphoCare study is interesting but doesn't carry sufficient weight to prompt changes.


"The NCCN guidelines process takes into account all new information that's available and it's rare that any one study other than a large Phase III randomized clinical trial results in a major and significant change," he said, adding that all of the options for treatment noted in the paper are included in the guidelines as options for this disease.


"The guidelines do not say 'only radiation therapy'; they say 'radiation preferred for stage I patients,' and they also include immunotherapy, chemotherapy, and combined-modality therapy."


Patient Selection Factors

The main criticism one should have about this study, Hoppe said, is that "there is absolutely no knowledge of how different treatments were chosen for different patients."


"The selection factors are totally unknown, and when you have half a dozen different treatments, there may be subtle selection factors-for example, a patient who had more of a concern with respect to vague symptoms, or problems with intercurrent disease that would have influenced choices of treatment, or a patient's refusal to accept a specific therapy.


"Or the availability of a modality: These patients were accrued at over 200 centers around the country, and perhaps at some of those centers certain treatments weren't available readily, or the patients couldn't get insurance authorization for one treatment or another."

RICHARD HOPPE, MD: T... - Click to enlarge in new windowRICHARD HOPPE, MD: "The main criticism one should have about this study, is that there is absolutely no knowledge of how different treatments were chosen for different patients."

Without knowledge of those selection factors, "to do a comparison of outcomes for those different treatments I think was inappropriate," he said.


He pointed out that there was a relatively high proportion of patients with Stage I disease in the study, whereas historically, one would expect Stage I and II combined to be only about 20 percent of patients with follicular lymphoma, while this study had 18 percent with Stage I alone.


In addition, although in the paper, the authors mention that since Stage I follicular lymphoma is an uncommon presentation, it would be difficult to do a randomized clinical trial, Hoppe disagreed.


"I wouldn't be such a nihilist about the possibility of doing a randomized, clinical trial," he said. "If the pharmaceutical companies responsible for this registry study wanted to do something really valuable, they would fund a randomized, clinical trial looking at some of the modalities currently being used for these patients to help us define if one or another is really better."


In fact, he said, an Australian cooperative trials group, the Trans Tasman Radiation Oncology Group, has just completed a trial (TROG 99.03) of about 150 patients with Stages I or II low-grade follicular lymphoma, randomizing between radiation therapy alone and either rituximab-chemotherapy or chemotherapy followed by radiation.


"They haven't reported results yet, that trial just closed, but they demonstrate that it is possible to conduct a clinical trial for patients with limited-stage follicular lymphoma," Hoppe said. "And that's really what should be done to answer these questions, because a registry study where you don't know what the selection factors are is not going to answer the question.


Hypothesis Generating

But another member of the NCCN panel, Julie Vose, MD, MBA, Professor of Internal Medicine in the Division of Hematology & Oncology at the University of Nebraska Medical Center, said the study definitely brings into question the recommendations and should serve as a hypothesis for future trials in this patient population.


"The data is definitely interesting, and I am sure this will be discussed at the next NCCN lymphoma guidelines committee meeting," she said in an e-mail exchange.


But she also pointed out that the registry data is not part of a monitored clinical trial, and would not be counted in the NCCN guidelines as Level 1 evidence, which is a randomized clinical trial.

JULIE VOSE, MD, MBA:... - Click to enlarge in new windowJULIE VOSE, MD, MBA: "This study will give us a lot of information for planning an appropriate clinical trial for the future."

And the finding that NCCN guidelines are not followed is multifactorial, Vose said. "There are patient-related issues, where the patient does not want treatment or they are concerned specifically about the radiation side effects or chemotherapy side effects. And there are physician issues where they may go by their own experience and not necessarily the guidelines or literature, or the physicians interpret the literature in a different way.


"In any case, I believe this article will give us a lot of information for planning an appropriate clinical trial for the future."


Editorial: Unresolved Issue of Radiation Therapy

In an accompanying editorial (JCO 2012;30:3328-3329), Silvia Montoto, MD, of Barts Cancer Institute of Queen Mary University of London, said, "We have complacently believed that the problem of stage I and II follicular lymphoma (FL) was solved and that we did not have to pursue additional investigation of the management of localized FL. Instead, what this study tells us is that the question that we thought we had answered (i.e., what is the standard treatment for patients with localized disease at diagnosis?) is still unresolved."


Furthermore, she continued, there are important questions that need to be answered in well-designed, clinical trials:


* What is the outcome of patients with a negative FDG-PET after an excision biopsy (stage 0) and who are managed expectantly in comparison with patients with stage 0 treated with the standard involved-field radiation therapy (IF-RT)?


* Does single-agent rituximab (or radioimmunotherapy) offer any advantage over IF-RT in patients with stage I FL?



"If the paradigm is to be changed, this change has to be driven by better evidence than that which has been used to support radiation therapy as the standard treatment for localized FL," she concluded.