'Watchful Waiting' for Early Follicular Lymphoma Questioned

Alexander M. Castellino, PhD

September 06, 2018

In a discussion of the treatment for early-stage follicular lymphoma (FL), a pair of experts question the wisdom of "watchful waiting" as a management option.  

The comments come from radiation oncologists Joanna C. Yang, MD, MPH, from the University of California at San Francisco and Joachim Yahalom, MD, from the Memorial Sloan Kettering Cancer Center in New York City.

The comments appear in an editorial published online August 28 in the Journal of Clinical Oncology, which was prompted by a report in the same journal, but published online a month earlier, already reported by Medscape Medical News.

That report was from the Trans-Tasman Radiation Oncology Group (TROG) 90.03 study. It showed that involved-field radiotherapy (RT) may cure less than 50% of patients with stage I or II FL, but adding systemic therapy provides better clinical outcomes. Treatment with rituximab and chemotherapy along with RT was associated with a dramatic improvement in 10-year progression-free survival (vs RT alone), but this became apparent only after 5 years, and the overall survival was not similar for both groups.

Watchful Waiting Questioned

Commenting on TROG 90.03 for Medscape Medical News in July, lymphoma expert Nadia Khan, MD, from the Department of Hematology/Oncology at the Fox Chase Cancer Center, Philadelphia, Pennsylvania, said, "While this [TROG 90.03] is a well-designed study, with statistically meaningful results, the conclusions are not clinically impactful because of practice trends in early stage FL."

Khan explained that patients with early-stage, low tumor burden FL are typically managed with watchful waiting. "Initiating treatment at early time points is reserved for specific scenarios, including nodal disease confined to a radiation treatment field," she said.

Referring to a Stanford University study, Khan explained that in these instances radiation provides 5-year and 10-year disease-free survival of 55% and 44%, respectively, and is the treatment of choice (J Clin Oncol. 1996;14:1282-1290).

However, in the editorial, Yang and Yahalom question the wisdom of watchful waiting as a management approach for early-stage FL.

They note that in TROG 90.03, patients receiving involved-field RT alone, 10-year progression-free survival was 41%. This observation suggests that that "there is a substantial subset of patients with early-stage FL who can be cured with RT alone, dispelling the notion that this disease is incurable," they note.

"This should only further dissuade oncologists from choosing observation (watchful waiting) for patients with early-stage FL, because observation alone has never been curative," they add.

Observation alone has never been curative. Dr Joanna C. Yang and Dr Joachim Yahalom


The editorialists note that watchful waiting was based on a small retrospective experience in 43 patients at a single institution in the pre–positron emission tomography era.

Concern for RT-related toxicity was based on outdated fields and doses, they argue.

The current RT of choice is 24 Gy of involved-site RT (ISRT), which is extremely well tolerated, they note. Even in patients with poor performance status or large-volume disease, low-dose ISRT of 4 Gy remains a viable and attractive option, they write.

Radiation for Early FL Underused

Yang and Yahalom note that in approximately 25% of patients diagnosed with early-stage FL, RT achieves local control in over 90% of lesions and close to 50% of patients remain lymphoma-free (ie, are cured) for decades.

The National Comprehensive Cancer Network recommends ISRT for early-stage FL for both stage I and contiguous stage II disease, they point out.

Yet, they say, RT for early-stage FL is underused.

In the Surveillance, Epidemiology, and End Results database and in the National LymphoCare Study, only 34% and 23% of patients, respectively, received RT as initial treatment for early-stage FL. The National Cancer Database showed a decrease of 13% in RT use, from 37% in 1999 to 24% in 2012.

So if RT use is decreasing, how are these patients with early-stage FL being treated?

In the National LymphoCare Study, 53% of patients received some form of systemic therapy, which included use of rituximab alone or in combination, and also RT, Yang and Yahalom note.

The editorialists write that systemic therapy is not yet the standard of care in early-stage FL. However, the National LymphoCare Study showed rituximab with chemotherapy was better than RT alone, and long-term follow-up from the MD Anderson Cancer Center showed that the combined modality of systemic therapy and RT achieved remission in 99% of patients, a 10-year time-to-treatment failure rate of 72%, and a 10-year overall survival rate of 80%

Factoring in Cost

Another issue to consider is cost, Yang and Yahalom comment.

According to the Government Accountability Office, in the United Sates, rituximab was the second-highest-expenditure Medicare Part B drug — accounting for $1.3 billion in expenditure in 2010 and $1.6 billion in 2015.

Hence, in designing an adjuvant study in early-stage FL comparing the combination of rituximab and RT with the combination of rituximab and chemotherapy, cost should be  considered. In fact, cost considerations should also be factored into any trial comparing older with newer regimens, they add, and should include any therapy used to manage adverse events.  

Currently, several treatment options are used during the long course of early-stage FL: low-dose RT, chemoimmunotherapy, and allogeneic transplant at relapse.

"The financial cost to the individual and to society using data emerging from new studies evaluating quality-adjusted life-years and cost effectiveness also need to be accounted for when choosing the initial, preferred treatment strategy," Yang and Yahalom conclude.

The editorialists have disclosed no relevant financial relationships.

J Clin Oncol. Published online August 28, 2018. Full text

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