Interim PET/CT Result Is The Sole Prognostic Factor Of Survival In Patients With Advanced-Stage Diffuse Large B-cell Lymphoma A Prospective Trial

Background: We assessed whether interim positron emission tomography (iPET) had a prognostic value for diffuse large B-cell lymphoma (DLBCL) and whether PET-driven intensiﬁed therapy was needed. Methods: A prospective analysis of newly diagnosed stage III-IV DLBCL patients treated was conducted. The iPET scan was performed after 4 cycles of RCHOP (rituximab 375 mg/m2 d1; cyclophosphamide 750 mg/m2 d2; doxorubicin 50 mg/m2 d2; vincristine 1.4 mg/m2 [maximum 2 mg] d2; prednisone 100 mg orally daily d2-6) in all cases. Patients received 2 additional cycles when they achieved complete response. If they achieved partial response (PR), they received 4 additional cycles, and a final PET scan (fPET) was performed. If they had stable disease or progressive disease (PD), they were excluded from the study. The primary endpoint was 3-year progression-free survival (PFS), and secondary endpoints included 3-year overall survival (OS) and objective response rate (ORR). The trial is registered with ClinicalTrials.gov, number NCT 01804127. Results: From 2013 to 2015, a total of 55 patients were enrolled and 53 with both baseline and iPET scans were analyzed for prognostic value. Thirty-nine patients had iPET-negative (iPET-) and 14 patients had iPET-positive (iPET+) scans (11 had PR and 3 had PD). The ORR was 94.3%. With a median follow-up time of 36.4 months, 3-year PFS was 65.7% and 3-year OS was 79.9% for the entire cohort (n=53), and the median PFS and OS were not yet reached. iPET-patients had a higher 3-year PFS rate (78.1%) than iPET+ patients (34.3%) with a P value lower than 0.01. A trend for improved OS was also observed, with 3-year OS of 87.1% versus 62.3% (P=0.03). All 11 patients who had iPET PR

4 had fPET-positive (fPET+) scans. The 3-year PFS did not differ significantly between the iPET-and fPET-patients. In the univariate analysis, iPET-was the sole independent prognostic factor for PFS. Conclusions: PET/CT has a good prognostic value in patients with advanced-stage DLBCL. There was little significant benefit to intensifying chemotherapy if the iPET scan was positive.

Background
Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of adult non-Hodgkin's lymphoma (NHL), and is associated with an aggressive clinical course. However, treatment failure is still an important problem as the 3-year progression-free survival (PFS) of DLBCL patients is approximately 60-70% after RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)-like treatments as first-line strategies [1,2].
The interim 18 F-fluoro-2-deoxy-D-glucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) scan (iPET) during first-line therapy has been validated as a strongest prognostic tool in advanced Hodgkin's lymphoma (HL), even offseting the role of traditional International Prognostic Score [3]. In advanced HL patients, better survival and life quality can be achieved, if using iPETdriven strategy. When iPET-negative (iPET-) indicates a good prognosis, doctors may downgrade the treatment such as removing Bleomycin, avoiding toxicity and second primary tumor [3]. And iPET-positive (iPET+) shows a poor outcome, early therapy intensification in response to positive iPET findings could improve the survival.
However, compared to the conventional ABVD regimen, intensified treatments such as BEACOPP and high-dose chemotherapy with autologous stem cell transplantation could result great toxicities [4]. The role of cytotoxic drugs is limited, so not all iPET+ patients can achieve complete response (CR) after intensified chemotherapy [5,6]. To further improve the outcome,such new therapies as brentuximab vedotin are needed.
In DLBCL, it is common to perform an iPET after 2 to 4 cycles of first-line chemotherapy. Whether or not patients with a positive iPET should receive a more intensive regimen as an immediate salvage treatment is still a topic of debate. We conducted an open-label, non-randomised, singal arm, phase 2 study of a cohort of DLBCL patients treated at a single academic medical center to examine the prognostic value of iPET for DLBCL. This study adhered to CONSORT guidelines.

Inclusion and exclusion criteria
Newly diagnosed stage III-IV DLBCL patients, age 18-80 years, were eligible for this study. All patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 and adequate hepatic, renal, and hematologic functions. Patients had at least one measurable target lesion. Patients with left ventricular ejection fraction less than 50%, which was evaluated by echocardiogram at baseline, were excluded. Patients with a history of severe heart disease, uncontrolled hemorrhage, or infection were also excluded. All patients provided written informed consent. Patients received 2 additional cycles of RCHOP when they achieved CR. If they achieved partial response (PR), they received 4 additional cycles of RCHOP, and a final PET (fPET) scan was performed on cycle 8 day 18 to day 20. If they had stable disease or progressive disease (PD), they were excluded from the study.

Treatment and response evaluation
After completion of therapy, patients were followed up every 3 months for the first 2 years, then every 6 months for 3 years.
The primary endpoint was 3-year PFS, and secondary endpoints included 3-year overall survival (OS) and objective response rate (ORR). PFS was defined as the interval between initiation of RCHOP treatment and disease progression or the last follow-up visit in remission. OS was calculated from the date of initiation of RCHOP treatment to the date of death from any cause or last follow-up.
Categorical variables are expressed as frequencies. Chi-square test or Fisher's exact test were applied to detect differences between groups. PFS and OS were compared using the Kaplan-Meier method and log-rank test, and a difference of P<0.05 was considered significant. All statistical analyses were performed using SPSS 17.0 software (SPSS Inc., Chicago, IL, USA). iPET-patients had a higher 3-year PFS rate (78.1%) than iPET+ patients (34.3%) with a P value less than 0.01. A trend for improved OS was also observed, with 3year OS of 87.1% versus 62.3% (P=0.03) (Fig. 1a,b). All 11 patients who had iPET PR received another 4 cycles RCHOP, and 10 of them underwent fPET. Six patients had fPET-negative (fPET-) and 4 patients had fPETpositive (fPET+) scans. The 3-year PFS or OS did not differ significantly between the iPET-and fPET-patients (78.1% vs 62.5%, P=0.64, 87.1% vs 83.3%, P=0.81) (Fig.   1c,d).
In the univariate analysis, iPET-was the sole independent prognostic factor for PFS in patients with DLBCL treated with RCHOP. No other baseline clinicopathologic 8 factors, including age, disease stage, gender, molecular subtype, B symptoms, ECOG PS, elevated lactate dehydrogenase (LDH), IPI score, or extra-nodal involvement, were predictive of PFS for the entire cohort. For this reason, multivariate analysis was not done.

Discussion
PET/CT is currently done for staging, assessment of remission and recurrence, and evaluation of therapeutic efficacy of patients with DLBCL [7]. The focus has generally been on whether PET can guide treatment escalation in poor responders to improve remission rates in NHL [8]. To date, in DLBCL, PET predicts response, but more intensive chemotherapy has failed to improve outcomes for patients with iPET+ scans [8,9]. Several large prospective studies such as the PETAL and LYSA trials demonstrated that treatment intensification such as the Burkitt-type approach or autologous stem cell transplantation fail to prevent iPET+ patients from having a higher risk of relapse than iPET-patients [10]. RCHOP-like chemotherapies have been proven to be effective in DLBCL for many years. Any alternative options will be considered only after being shown to be superior to the ongoing treatment. In this study, patients who had iPET PR were treated with 4 further RCHOP cycles. If they achieved fPET CR, they had a similar good outcome to iPET-patients. Only patients with fPET+ scans had inferior PFS and OS. This study demonstrates no inferiority of continuation of the first-line regimen in patients with iPET PR. So, when aiming to maximize cure while minimizing toxicity, there is no need to escalate treatment of iPET+ patients.
Over the past decades, the IPI has become the most commonly used prognostic index in DLBCL patients [11,12]. The IPI can differentiate DLBCL patients into distinct risk groups for survival after RCHOP. More recently, iPET has shown high predictive value in HL. It has been validated as a strongest prognostic tool in advanced HL, even offseting the role of traditional IPS. iPET-could indicate a good prognosis, and iPET+ could indicate a poor outcome, regardless of gender, stage, age or count of hemoglobin and lymphocyte [5,13]; however, many studies focusing on the role of iPET in PFS prediction have been done, with conflicting results [14][15][16][17][18][19][20].
From these studies, it can be concluded that phenotypic and genotypic heterogeneity of DLBCL, heterogeneity in patient populations, therapy regimens, PET scanners, and timing and interpretation criteria of iPET scans made it hard to clarify the accuracy of iPET to predict clinical outcome in DLBCL.
Recently, several studies have shown that PET/CT was a more valid prognosticator of survival for patients with DLBCL than traditional clinicopathologic factors such as IPI score [21][22][23][24][25]. Our results confirm that only iPET was a significant independent indicator of outcome for patients with DLBCL in the rituximab era. iPET-patients had a higher PFS rate and OS rate than iPET+ patients with a statistical significance.
There are some limitations to this study. First, this study was a single-arm, small-    CONSORT checklist.pdf