Joanna C. Yang, MD, MPH
Joachim Yahalom, MD
Radiation therapy for early-stage follicular lymphoma “is underused,” Joanna C. Yang, MD, MPH, and Joachim Yahalom, MD, declared in a recent editorial in the Journal of Clinical Oncology.1 This underuse of radiation therapy can result in overtreatment with systemic therapies or overconfidence in observation, which, the authors noted, “has never been curative.”
“The majority of patients with early-stage follicular lymphoma are not receiving appropriate treatment because follicular lymphoma in general, is considered to be incurable; this concept is wrong for patients with localized disease. This disease is curable for a significant number of patients,” Dr. Yahalom stated in an interview with The ASCO Post. “Some patients may be overtreated, experiencing unnecessary toxicity, by avoiding a simple, cost-effective treatment,” which, he added, “would be radiation therapy at low-dose and to a limited field.”
Dr. Yahalom is Attending Radiation Oncologist at Memorial Sloan Kettering Cancer Center and Professor of Radiation Oncology at Weill Cornell Medical College, New York. He is also Chair of the International Lymphoma Radiation Oncology Group. Dr. Yang is Assistant Professor, Department of Radiation Oncology, University of California, San Francisco, and was Chief Resident at Memorial Sloan Kettering Cancer Center and worked collaboratively with Dr. Yahalom when they wrote this editorial.
Treatment for Many Is Contrary to Guidelines
The National Comprehensive Cancer Network® (NCCN®) recommends involved-site radiation therapy for early-stage follicular lymphoma. “The recommendation is clear, and the whole team of about 20 representatives of the major centers all agreed that this is the tried and true treatment,” Dr. Yahalom said.
Surveillance, Epidemiology, and End Results (SEER) data, however, show that only 34% of patients with early-stage follicular lymphoma received radiation as their initial treatment, and the National LymphoCare study found only 23% of patients did. “Furthermore,” the editorial noted, “the National Cancer Database showed a 13% decrease in the use of radiation therapy, from 37% in 1999 to 24% in 2012.”
“The question is why do we see in the national databases that only between one-quarter and one-third of patients are getting the treatment recommended by the NCCN, and some are not getting treated at all. They are observed and then eventually experience disease progression, and some are getting other treatments that are more costly and more toxic,” Dr. Yahalom said.
Not Everyone Needs Systemic Therapy
The editorial commented on a report, published in the Journal of Clinical Oncology earlier online,2 on the TROG 99.03 trial. A total of 150 patients, enrolled between 2000 and 2012, were randomly assigned to receive either 30 Gy of involved-field radiation therapy alone or with 6 cycles of cyclophosphamide, vincristine, and prednisone (CVP), with rituximab (Rituxan) added in 2006 (R-CVP). The investigators concluded that systemic therapy with chemotherapy or chemoimmunotherapy after radiation therapy “reduced relapse outside radiation fields [and] significantly improved progression-free survival.”2 Ten-year progression-free survival was 59% for those receiving combination therapy vs 41% for those receiving radiation alone.
“Of note, the progression-free survival for the study arms only began to separate to approximately 5 years, reflecting the indolent nature of the disease,” Drs. Yahalom and Yang wrote. “It is a slow-growing disease, so it really takes time until another site will appear,” Dr. Yahalom elaborated. “That is why this disease should be managed gently and not aggressively, because it is engaging patients, especially older patients, for many years.”
The 10-year progression-free survival rate of 41% among patients receiving radiation alone provided evidence “further supporting the idea that there is a substantial subset of patients with early-stage follicular lymphoma who can be cured with radiation therapy alone and dispelling the notion that this disease is incurable,” Drs. Yahalom and Yang wrote.
“What we learned is that additional therapy may be better for a subgroup of patients that now can be more easily identified, but for the majority of patients, I doubt this is necessary,” Dr. Yahalom told The ASCO Post. In more recent times, he explained, patients are treated based on positron-emission tomography (PET) and computed tomography (CT) scanning. In the TROG 99.03 study, however, only 48% of the patients were staged with PET scans at randomization. “Not surprisingly, the researchers in the TROG 99.03 study found that PET staging was associated with superior progression-free survival, likely because of stage migration and more accurate radiation therapy planning,” the editorial noted.
Observation Is Never Curative
The findings of TROG 99.03 “should only further dissuade oncologists from choosing observation (watchful waiting) for patients with early-stage follicular lymphoma. Observation has never been curative and, further, is solely based on a small retrospective experience of 43 select patients at a single institution in the pre-PET era,” the editorial noted.
That study, published in the Journal of Clinical Oncology in 2004, was a retrospective analysis of 11 patients with stage I and 32 patients with stage II follicular lymphoma whose therapy was deferred for at least 3 months after diagnosis.3 “At a median follow-up of 86 months, 27 patients (63%) had not been treated,” the study authors noted. They concluded that “deferred therapy is an acceptable approach, as more than half of our patients remained untreated at a median of 6 or more years, and survival was comparable to that seen in reports with immediate treatment.”
“To make a conclusion for the whole country, based on sporadic patients, I think was wrong,” Dr. Yahalom said.
“In that study, the most common reasons cited for no initial therapy were physician choice, followed by concern for radiation therapy–related toxicity on the basis of -outdated fields and doses,” Drs. Yahalom and Yang wrote. “However, involved-site radiation therapy of up to 24 Gy is extremely well tolerated, with only a 3% incidence of acute grade 3 to 4 toxicities. Furthermore, in patients for whom radiation therapy–related toxicity is a true concern because of poor performance status or large volume of disease, low-dose involved-site radiation therapy of 4 Gy remains a viable and attractive option.”
Switch From Involved-Field to Involved-Site Radiation Therapy
As noted in the editorial, during the time the TROG 99.03 trial was being conducted, “standard radiation therapy fields changed from involved-field radiation therapy to involved-site radiation therapy.” This is one of a series of changes in radiation therapy for follicular lymphoma. “All the old studies have treated multiple lymph node sites, even if they were not involved,” Dr. Yahalom explained. “Then we switched to treatment of regional sites in the body, which was again a smaller region like the neck. Now, if there is one lymph node in the neck, we just treat this lymph node. This is involved-site radiation therapy, and the morbidity is significantly lower.”
One of the major concerns centered on maintaining the option to give other treatments if needed later. “What if we need to give chemotherapy and we’ve wiped out the bone marrow with radiation to almost the whole body? That is not an issue anymore. The involved site is an easy field to define with modern imaging. It limits the volume and the amount of radiation significantly,” Dr. Yahalom said.
Reduced Radiation Dose for Indolent Disease
“There are other changes that have been going on with dose that are important to note,” he continued. Over the years, the radiation dose for patients with indolent lymphoma has been reduced from 40 Gy to 24 Gy, with “the exact same excellent results,” Dr. Yahalom noted. “Now we are actually giving 4 Gy, 2 days of radiation, which we call ‘boom-boom,’ and for about 70% of the patients, that is all they need. That is effective as a treatment and is sometimes my first choice,” Dr. Yahalom said.
“These are dramatic changes,” he emphasized. “In terms of side effects, it’s nearly like not getting any radiation. Still, indolent lymphoma has a 70% complete and lasting response. And you can always repeat if you need to.”
The lower-dose radiation “is also excellent for patients who relapsed, failed to respond to chemotherapy, and have one or two areas that are symptomatic,” Dr. Yahalom said. “Instead of sending them to another phase I study, with a new drug and unknown side effects, you just ask them to come twice and 70% of the time,” he said, those symptomatic involvements “will disappear without bothering the patient.” Currently, he said, the full potential of that option is not being realized.
Dr. Yahalom explained that the 4-Gy dose was pioneered in Europe and is more commonly used there. “Now it is used also in some of the major centers in the United States,” he said, although its use has not yet extended to smaller hospitals and practices.
Consideration of Nonstandard Treatment
The 4-Gy option is not currently included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), but Dr. -Yahalom advocates that it should be. “Right now, the NCCN Guidelines suggest that the treatment of choice is 24 Gy of radiation therapy,” Dr. Yahalom noted. “There are situations, however, that I offer patients in discussion. I tell them that it is not the standard treatment, but they can choose to have 4 Gy, come back in 10 weeks, and we will repeat the PET or CT scan,” he said.
Patients can still receive the high-dose treatment of 24 Gy, but “to some patients, especially those who are old and frail, if they live far away and we find them reliable in terms of coming back for staging or imaging, 4 Gy is a reasonable option,” and often “patients are enthusiastic about this,” Dr. Yahalom said.
“When you use it, you see the benefit. When these patients go back to their medical oncologists, they keep sending more and more patients [for this treatment]. But it is a matter of promoting a modality that is not in the spotlight. It is not a new curing drug,” but it is a treatment that “helps the patient at low cost,” Dr. Yahalom commented. It is an option, certainly as palliation, and in my opinion, also an option as a first-line treatment. It is better than observation, and it is certainly less toxic than any other treatment I know.”
Cost-Effectiveness of Radiation Therapy
The long disease course of follicular lymphoma mandates consideration of the costs of treatments. At the 2017 ASCO Annual Meeting, Dr. Yang presented a cost-effectiveness analysis of different first-line treatments used for early-stage follicular lymphoma: radiation therapy to 24 to 30 Gy; observation; rituximab induction; rituximab and bendamustine; and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).4
Compared with rituximab induction, first-line radiation therapy “resulted in an incremental cost-effectiveness ratio of $2,740 per quality-adjusted life year,” according to the analysis. “The probability of dying from other causes, the probability of a complete response to radiation therapy, and the probability of relapse had the greatest impact on both cost and effectiveness expected values.”
The study concluded that radiation therapy “is the most effective upfront treatment” for patients with early-stage, low-grade follicular lymphoma and that first-line radiation therapy “paired with R-CHOP for relapses is a cost-effective treatment paradigm, relative to other strategies.”4
“Even compared to observation, radiation therapy was less expensive,” Dr. Yahalom explained, because eventually, patients who were observed needed more frequent studies, such as CT scans, and “relapsed more often in situations where they needed more expensive treatment, including bone marrow transplant. -Basically, doing a little radiation first, is more cost-effective,” he said. “The patients gain more years of quality life with less cost than observation or rituximab.”
“The cost-effectiveness model that we built was looking at standard treatment, which is still 24 Gy. It was not looking at the very low–dose radiation. It would be interesting to model a 4-Gy option as well,” Dr. Yang told The ASCO Post. “That is in the works. But the bottom line from what we have done already, is that standard involved-site radiation for early-stage follicular lymphoma is actually cost-effective.” ■
DISCLOSURE: Drs. Yang and Yahalom reported no conflicts of interest.
REFERENCES
1. Yang JC, Yahalom J: Early-stage follicular lymphoma: What is the preferred treatment strategy? J Clin Oncol 36:2904-2906, 2018.
2. MacManus M, Fisher R, Roos D, et al: Randomized trial of systemic therapy after involved-field radiotherapy in patients with early-stage follicular lymphoma: TROG 99.03. J Clin Oncol 36:2918-2925, 2018.
3. Advani R, Rosenberg SA, Horning SJ: Stage I and II follicular non-Hodgkin’s lymphoma: Long-term follow-up of no initial therapy. J Clin Oncol 22:1454-1459, 2004.
4. Yang JC, Elkin EB, Parikh R, et al: Cost-effectiveness analysis of first-line treatments for early-stage, low-grade follicular lymphoma. 2017 ASCO Annual Meeting. Abstract 6619. Presented June 5, 2017.
