PET-Guided Therapy Improves Outcomes in Patients With Limited-Stage DLBCL

Use of interim positron emission tomography (PET) scans to direct patient care has established a new standard treatment approach for patients with limited-stage diffuse large B-cell lymphoma (DLBCL). These findings, from the Intergroup, National Clinical Trials Network S1001 study, were reported in the Journal of Clinical Oncology.¹

DLBCL is the most common type of non-Hodgkin lymphoma in the United States. About 25% to 30% of patients with this malignancy will present with limited-stage disease. These patients have better overall survival (OS) rates than patients with advanced disease; however, they also face the constant risk of relapse.

Lead author Daniel O. Persky, MD, of the University of Arizona Cancer Center, and colleagues noted that their previous work conducted prior to the approval of rituximab (Rituxan) found that 3 courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), followed by radiation therapy, led to better overall and progression-free survival rates in patients when compared to 8 courses of CHOP without radiation.² Unfortunately, Persky and colleagues found that by year 9, the difference between the 2 regimens disappeared due to late relapses. Further research led to the stage-modified International Prognostic Index (sm-IPI), which enabled physicians to determine whether a particular patient had adverse risk factors. Those risk factors had a major impact on prognosis; the OS rate at 10 years in patients without risk factors was 89%.³

More recently, though, rituximab has led to a major shift in the treatment of DLBCL. In high-risk patients, 3 cycles of R-CHOP followed by radiation therapy became the standard treatment, Persky and colleagues noted. Following up that therapy with radioimmunotherapy consolidation with ibritumomab tiuxetan (Zevalin) has been shown to decrease the rate of long-term relapse.

Persky et al noted that PET scans have been shown to be prognostic as an interim assessment, and some data have suggested that patients with negative PET scans have a low risk of relapse if they undergo a final round of R-CHOP and forgo radiation therapy.

In order to evaluate that premise, Persky and colleagues enrolled 158 patients, of whom 128 ultimately underwent central review of their interim PET/CT scans. All of the patients had nonbulky (<10 cm) stage I/II untreated DLBCL and received 3 cycles of R-CHOP therapy, after which the scans were taken.

If the scans were negative, patients were given one more cycle of R-CHOP. If a patient’s scan was positive, they were given field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy.

Only 14 patients (11%) had positive interim PET scans following the initial 3 rounds of R-CHOP. After a median follow-up of 4.92 years, just 6 patients had relapses and 3 had died as a result of lymphoma, though an additional 11 died of causes unrelated to the cancer. The median age of those patients was 80 years. The median age in the overall trial was 62 years.

Persky told Targeted Oncology that the use of PET as an interim assessment would be a new strategy for many in the field. “Physicians treating lymphoma are using PET scans frequently for staging and response assessment, but their use in directing treatment at interim assessment is more controversial,” he said. “S1001 showed that interim PET could be used successfully to guide further therapy, and thus does represent somewhat of a shift.”

Persky et al found a 5-year progression-free survival (PFS) rate of 87%; 5-year OS rate was 89%. The authors reported that the OS and PFS rates were similar in both groups—those with negative scans who underwent another R-CHOP cycle and those with positive scans who subsequently had radiation therapy.

Persky and colleagues said their study is believed to be the largest prospective study of patients with limited-stage DLBCL in the United States since the introduction of rituximab.

“The trial establishes R-CHOP x 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients,” they concluded, as the study also showed good outcomes for older patients and those with bulky disease.

Persky and his colleagues conceded that their overall PFS rate was lower than their original goal of 93%. However, they said that shortcoming does not affect their overall conclusions, given the high risk of death among the age group.

“Considering these competing risks of death in an older population over a prolonged time period, we feel that the traditional end point of PFS does not adequately reflect the observed treatment effects, which was supported by our competing risk modeling,” they wrote.

The investigators also noted that not only did patients with positive interim PET scans end up with similar PFS and OS rates, but also no patient in that group had experienced a relapse as of the end of the study.

“We used a relatively high radiation dose (36 Gy plus a 9 Gy boost vs30-35 Gy in other studies) and a larger radiation field (IFRT [involved-field radiation therapy] vsinvolved-site RT) for these patients, which is no longer standard,” the study authors wrote. “In addition, ibritumomab tiuxetan is not approved in DLBCL. However, ibritumomab tiuxetan could have eliminated residual disease through the crossfire of radioisotope.”

The authors suggested that additional research would be needed to verify the outcomes among this group due to the small sample size in the current study.

_References:

_{1. Persky DO, Li H, Stephens DM, et al. Positron Emission Tomography-Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001. J Clin Oncol. Published online July 13, 2020. doi:10.1200/JCO.20.00999}

_{2. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med. 1998;339(1):21-26. doi:10.1056/NEJM199807023390104}

_{3. Shenkier TN, Voss N, Fairey R, et al. Brief chemotherapy and involved-region irradiation for limited-stage diffuse large-cell lymphoma: an 18-year experience from the British Columbia Cancer Agency. J Clin Oncol. 2002;20(1):197-204. doi:10.1200/JCO.2002.20.1.197}