The prognostic value of PET scan in the treatment of DLBCL

Positron emission tomography (PET)-computed tomography (CT) is considered as having a prognostic value in the treatment of diffuse large-B cell lymphoma (DLBCL). A positive or negative PET-CT scan after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and disease stage-dependent consolidative radiation therapy (RT), may guide treatment decisions, improve outcomes, and safeguard patients from RT-associated adverse events.¹ The controversy around the use of RT in patients with advanced-stage DLBCL remains, and thus, there is a great need for distinguishing patients requiring RT from those with low-risk disease that could be spared.²

Two different studies have investigated the outcomes of PET-guided treatment decisions in patients with limited-stage DLBCL (S1001 study, NCT01359592)¹, and those with advanced-stage DLBCL². We hereby combine and summarize the key points of those two studies.

Limited-stage DLBCL¹

DLBCL appears as a limited-stage disease in 25–30% of patients and is associated with a better overall survival (OS) compared with advanced-stage disease. Three cycles of R-CHOP followed by RT represent the standard of care based on the recommendations of the National Comprehensive Cancer Network (NCCN). Persky et al., investigated in a prospective phase II trial (S1001) the impact of subsequent therapies after a positive or negative PET in patients ≥ 18 years of age who

• were previously untreated
• had non-bulky (< 10 cm) stage I/II CD20-positive DLBCL 
• had a World Health Organization performance status (WHO PS) of 0–2
• had a negative bone marrow biopsy within 6 weeks of registration

The primary endpoint was progression-free survival (PFS) at 5 years, and secondary endpoints included OS rate, PET subgroup outcome analysis, safety, and response rates.

Methods

Patients were treated with three cycles of standard R-CHOP treatment based on the dosing schedule shown in Figure 1, and then had an interim PET-CT scan at Day 15 and 18 of Cycle 3. A final PET scan was done 12 weeks after the end of treatment, and patients were monitored every 6 months during the first 2 years, and annually thereafter for up to 7 years or death.

Figure 1. Treatment schedule¹

FDG, fluorodeoxyglucose; IFRT, involved-field radiation therapy; IV, intravenously; PET, positron emission tomography; PO, orally; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. 

Patients

The number of eligible patients included in the trial was 132, with a median age of 62 years (range, 18–86). Patient characteristics are summarized in Table 1.

Table 1. Patient characteristics in the S1001 trial¹

 Of the 132 patients, 128 had their interim PET scans reviewed:

• 110 were negative
• 18 patients were positive; four due to infection but treated as PET-negative with one more R-CHOP cycle

• Of the 14 PET-positive patients (11%), 12 received involved-field radiation therapy (IFRT) and ibritumomab tiuxetan with eight of them achieving complete response (67%; CR), and four achieving partial response (33%; PR)

Outcomes

Median time from diagnosis to treatment was 31 days. Almost all patients (98%) completed the R-CHOP treatment as planned. Median follow-up was 4.92 years (range, 1.1–7.7). Survival outcomes and response rates are shown in Table 2.

Table 2. Outcomes from the S1001 trial¹

Six patients had disease progression with a median time-to-progression (TTP) of 1.1 years (range, 0.2–6.2), and three died in the PET-positive subgroup. Eleven patients with a median age of 80 years (range, 56–86) died due to causes not related to lymphoma. The most common Grade ≥ 3 adverse events were of hematological nature (42%). All Grade ≥ 3 adverse events are presented in Table 3. Two Grade 3–4 neutropenia, and three Grade 3–4 thrombocytopenia events were seen in patients receiving IFRT and ibritumomab tiuxetan.

Table 3. Grade ≥ 3 adverse events from the S1001 trial¹

Conclusion

In this trial, PET-adapted therapy led to favorable outcomes for both PET-negative and PET-positive patients in the long-term. PET-negative patients who were spared from RT and received an additional cycle of R-CHOP had similar PFS and OS results to those with a positive PET scan who received consolidative RT. These findings suggest that PET can guide treatment decisions in patients with limited-stage DLBCL.

Advanced-stage DLBCL²

A common approach for the treatment of advanced-stage DLBCL includes six to eight cycles of R-CHOP with consolidative RT considered in patients with bulky disease or residual disease following immunochemotherapy. Freeman et al.² conducted a retrospective study to evaluate the value of end-of-treatment (EOT) PET scanning for considering RT consolidation in advanced-stage DLBCL patients based on a 14-year experience.

Methods and patients

Patients included in this study were ≥ 18 years of age with advance-stage DLBCL and must have received R-CHOP followed by EOT PET within 4–6 weeks of therapy completion. Three-year estimates for TTP, and OS outcomes were compared among different subgroups.

The number of patients included in the analysis was 723 with a median age of 65 years (range, 18–89) and the majority (74%) had Ann Arbor disease stage III–IV. Upon completion of therapy, 72% of patients were PET-negative while 28% had a positive PET scan. The vast majority of patients (94%) received 6 cycles of R-CHOP. Patient characteristics for the total population and by PET subgroups are provided in Table 4.

Table 4. Patient characteristics among groups²

Outcomes

With a median follow-up of 4.3 years (range, 0.9–14.2), the following outcomes were observed for PET-negative versus PET-positive patients:

• 3-year TTP: 83% (95% CI, 80–86) vs 56% (95% CI, 49–63), p < 0.001
• 3-year OS: 87% (95% CI, 84–90) vs 64% (95%, 57–70), p < 0.001

Of the 206 patients with an EOT PET-positive scan, 53% received consolidative RT. The following outcomes were observed for this subgroup:

• 3-year TTP was 76% (95% CI, 66–83) in patients who received consolidative RT and 34% (95% CI, 25–44) in patients who did not receive RT (p < 0.01). There was no statistically significant difference between PET-positive patients treated with RT and PET-negative patients in terms of TTP (p = 0.3)

• 3-year OS were:

• 87% (95% CI, 84–90) for patients with negative PET scan
• 80% (95% CI, 71–87) for patients with positive PET scan treated with RT
• 44% (95% CI, 34–54) for patients with positive PET scan not treated with RT

Of the patients who did not receive RT in the PET-positive group, 30% did not relapse compared with 27.5% of patients in the RT receiving PET-positive group.

Conclusions

This study showed that a negative EOT PET scan without RT consolidation was associated with a 3-year relapse-free survival in 83% of patients with advanced-stage DLBCL. This indicates that such patients with a negative EOT PET can be spared from RT and its side effects without compromising their outcomes.

The results from both studies presented above, are supportive of an imaging-guided treatment approach where RT consolidation is decided based on PET scan results following completion of R-CHOP induction therapy in both limited- and advanced-stage DLBCL.