Can CT Alone Cure Early-Stage Hodgkin's Lymphoma?

Alexander M. Castellino, PhD

April 22, 2015

In most countries, the current standard of care in the treatment of early-stage Hodgkin's lymphoma — chemotherapy (CT) followed by radiation therapy (RT) — has provided cure rates of greater than 90%. But do all these patients really require RT, which is associated with late toxicity that undermines quality of life and long-term survival? It all depends on who one asks.

Investigators of the RAPID trial, published April 23 in the New England Journal of Medicine, report that patients with stage IA or IIA Hodgkin's lymphoma and a negative positron emission tomography (PET) finding after three cycles of CT had a good prognosis regardless of whether or not they received consolidation RT.

Corresponding author John Radford, MD, from the Institute of Cancer Sciences at the University of Manchester, in the United Kingdom, told Medscape Medical News: "Given that the current standard of care for these patients is CT followed by RT, RAPID set out to examine whether it was possible to avoid RT after CT in patients achieving complete remission, as measured by PET imaging."

The question posed by RAPID was an important one, he noted. "Although patients receiving the current standard of care are cured, they face life with an increased risk of long-term toxicity from the radiation [such as second cancers and premature coronary artery disease]," he added.

"What are we to conclude from this study?" ask Dan L. Longo, MD, and James O. Armitage, MD, in an accompanying editorial. Dr Longo is from Harvard Medical School and the Dana-Farber Cancer Institute, Boston, Massachusetts, and Dr Armitage is from the Division of Hematology-Oncology, University of Nebraska Medical Center, in Omaha.

Dr Armitage told Medscape Medical News: "This is an important study and raises questions on how to care for patients with early-stage Hodgkin's lymphoma."

It is a provocative study, but the interpretations will be controversial both among physicians and patients, he added.

The RAPID Study

The RAPID study enrolled 602 patients with stage IA or IIA Hodgkin's lymphoma at 94 centers in the United Kingdom.

After three cycles of chemotherapy (ABVD: adriamycin, bleomycin, vinblastine, dacarbazine), patients underwent a PET scan, which was read at a central facility.

Patients who did not achieve a complete remission (defined as a score of 1 or 2 on a 5-point scale) received a fourth round of ABVD and involved-field radiation.

Patients who achieved a complete remission were randomly assigned to receive no further therapy (n = 211) or RT (n = 209).

Routine clinical evaluation was undertaken every 3 months in year 1, every 4 months in year 2, and every 6 months in year 3. After year 3, patients were evaluated annually.

Computed tomography scans were required per protocol only at 6, 12, and 24 months.

The trial was a noninferiority trial originally designed to have a noninferiority margin of 10 percentage points in progression-free survival (PFS) — the group receiving RT and CT would have a PFS of better than 10 points compared with the group receiving CT alone.

However, on the basis of a 200-delegate survey undertaken at the 7th International Symposium of Hodgkin's Lymphoma, in 2007, the noninferiority margin was reduced to 7% — making the endpoint even more stringent. The change in the noninferiority margin has immediate implications for RAPID's meeting its primary endpoint.

RAPID Did Not Meet the Noninferiority Endpoint: Does It Matter?

With a median follow-up of 60 months, for the primary endpoint in the 420 patients who were randomly assigned to the study group, the 3-year PFS was 94.6% (95% confidence interval [CI], 91.5% - 97.7%) for patients in the RT group and 90.8% (95% CI, 86.9% - 94.8%) for patients in the group requiring no further therapy.

The 3-year absolute risk difference was -3.8% (95% CI, -8.8% to 1.3%). Explained the editorialists: "Because 8.8 [lower limit of the 95% CI] is more than 7 [the statistical noninferiority margin], the noninferiority margin was exceeded."

According to Dr Longo and Dr Armitage: "[The] 7 percentage points [is] a number that has no basis in experimental treatment results."

However, had the study protocol not amended its noninferiority margin, it would have met its primary endpoint.

Regardless of the study statistics, the results will be interpreted differently by different physicians, Dr Armitage told Medscape Medical News. Although the statistical interpretation changes, the numbers remain the same, he said.

In their editorial, Dr Longo and Dr Armitage indicate that approximately 18 of 20 patients who have negative PET findings are cured after three cycles of CT. Adding RT to CT cures an additional patient ― so that approximately 19 of 20 patients are cured.

However, they pointed out that 100 patients need to be exposed to RT to keep four patients from relapsing — all this with no evidence of long-term survival benefit. These observations have implications for treating early-stage Hodgkin's lymphoma patients, they emphasize.

Will Results From RAPID Change Clinical Practice?

Is RT following CT worthwhile for patients with early-stage Hodgkin's lymphoma? Therein lies the controversy.

Dr Armitage pointed out that for physicians and patients who prefer a cure at first treatment, this study will indicate that RT after CT will provide patients with a better chance for a cure. For those who prefer to avoid the long-term effects of RT, this study indicates that RT does not offer a significant advantage.

Physicians prejudiced against RT will use data from the RAPID study to bolster their argument; but so will those who favor RT, Dr Armitage added.

Dr Radford agreed with the editorial analysis and told Medscape Medical News: "Regardless of noninferiority not being met, both groups of patients did remarkably well."

He also agreed that patients should be involved in making the decision of whether or not they choose to receive RT after being informed of its risks and benefits.

"The main focus in treating these patients is to maximize cure and minimize toxicity," he added.

The main to maximize cure and minimize toxicity. Dr John Radford

Dr Radford told Medscape Medical News that patient factors often come into play when treating early-stage Hodgkin's lymphoma. For patients aged 70 years and older, RT following CT is a good option, because risk for relapse and the consequent requirement for salvage therapy is a greater threat. For a 20-year-old woman with stage IIA Hodgkin's lymphoma, risk for secondary tumors, especially breast cancer, and premature cardiac disease later in life is a real threat. For such patients, CT alone may be the preferred option in those achieving PET negativity.

Dr Armitage agreed. "The risk of breast cancer late in life is a real threat for women with early-stage Hodgkin's lymphoma who have RT to the breast," he said.

He told Medscape Medical News: "Given the abundance of data, early-stage Hodgkin's lymphoma may seem straightforward to treat. However, in practice, it is already individualized, based on patient characteristics."

In the United States, many oncologists are already using only CT, he added.

Dr Radford indicated that RAPID is ongoing and that patients will be followed for more than 10 years.

"Future studies in early-stage Hodgkin's lymphoma demand long-term follow-up," he said. Adverse effects, such as second tumors, do not manifest in patients until later in life, he indicated.

Dr Armitage commented that the RAPID investigators should be complimented on undertaking a brave study and seeing it to its completion.

The investigators have reported no relevant financial relationships.

N Engl J Med. 2015;372:1598-1607.


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