The I-PET/CT manifestation during induction chemotherapy has been demonstrated to be an independent prognostic indicator in DLBCL, compared with pretherapeutic indices, such as IPI[7]. Interim restaging is performed to identify patients whose disease has not responded to or has progressed despite induction therapy. However, previous studies have mainly included patients who underwent PET/CT during 2 to 5 cycles of chemotherapy, and these studies do not provide convincing evidence; furthermore, there is no consensus on how to monitor DLBCL patients during induction chemotherapy with first-line therapies[2–8]. Although the National Comprehensive Cancer Network (NCCN) guidelines do not recommend surveillance imaging for these individuals, PET/CT is widely used in clinical practice to monitor them. In the present study, we analyzed a homogeneous cohort of newly diagnosed DLBCL patients treated with R-CHOP who underwent PET/CT after every 2 cycles of chemotherapy, using the IHP consensus response criteria. Patients with negative PET/CT2 scans (n = 110) had significantly higher CR (97.3% vs. 33.3%), 3-year PFS (75.8% vs. 38.2%), and 3-year OS rates (93.5% vs. 55.6%) than those with positive PET/CT2 scans (n = 87). Patients with negative PET/CT4 scans still had higher CR (96.9% vs. 16.2%), 3-year PFS (75.3% vs. 24.7%), and 3-year OS rates (91.6% vs. 49.4%) than those with positive PET/CT4 scans.

Because cytotoxic chemotherapy is thought to kill cancer cells according to first order kinetics, after 2 cycles of chemotherapy in an idealized setting (assuming no interval tumor regrowth) one would expect a 99.9% reduction in the number of viable cancer cells[11]. Most of the therapeutic effects occur upstream; therefore, an index that reflects reduced metabolism in the assessment of chemosensitivity is expected to be more discriminating after 2 cycles of chemotherapy than after 4 cycles. In our series, 110 patients had negative PET/CT2 scans, and 87 had positive PET/CT2 scans according to the IHP criteria. Of the 110 PET/CT2-negative patients, all had negative PET/CT4 scans. Among the 87 PET/CT2-positive patients, 15 showed progression of the disease at PET/CT4. However, if the PET/CT2 findings were disregarded, only 7 of these patients would be considered to have progressive disease by comparing their PET/CT4 scans with their PET/CT0 scans; the remaining 8 patients would be considered as being in PR. Following the NCCN guidelines, treatment may have been delayed in these 8 patients if they had not undergone PET/CT2. Our results indicate that I-PET/CT should be performed after 2 rather than 4 cycles of immunochemotherapy in DLBCL patients.

Because of the risk of disease relapse, many lymphoma centers use routine surveillance imaging, such as CT or PET/CT, to detect relapse early, given the aggressiveness of this type of lymphoma. However, less than one-third of recurrences are detected at an asymptomatic stage. Even intensive scheduled surveillance by PET/CT did not ensure the early identification of most recurrences, which were detected in the presence of pre-existing symptoms[12–15]. Interestingly, the outcome in asymptomatic patients appeared to be similar to that reported for symptomatic subjects[14,15]. In the present study, among the 110 patients with negative PET/CT2 scans, all remained negative at PET/CT4, and only 3 were positive at F-PET/CT. In 2 of these 3 patients, treatment had been delayed because of drug toxicity. For PET/CT2-negative patients, the CR rate reached 97.3%, and the 3-year PFS and OS rates were as high as 75.8% and 93.5%, respectively. DLBCL patients who survive this long are likely to have been cured. Thus, we believe that the role of subsequent PET/CT in patients with negative PET/CT scans after 2 cycles of chemotherapy is limited and that the current strategy increases the financial burden on these patients. Furthermore, repeated surveillance imaging increases patients’ exposure to radiation and can potentially increase their risk of second malignancies[16,17]. One study has reported that routine surveillance imaging in long-term survivors of adult aggressive lymphoma exacerbates the underlying anxiety symptoms and fear of disease relapse or recurrence and negatively affects patient-physician communication[18].

I-PET/CT is performed to identify patients whose disease has not responded to or has progressed despite induction chemotherapy. However, I-PET/CT can give false-positive results, and some patients have a favorable long-term outcome despite a positive I-PET/CT scan. PFS in patients who were PET/CT4-positive and biopsy-negative was identical to that in PET/CT4-negative patients[5]. Therefore, I-PET/CT is not recommended for use in guiding decisions about changes to therapy[4]. In the present study, among the 87 PET/CT2-positive patients, 30 (34.5%) were negative at subsequent scans (19 at PET/CT4, and 11 at F-PET/CT). Although no biopsies were performed, a relatively large number of false-positive findings persisted. There are several potential explanations for false-positive scans. As a marker, ¹⁸F-FDG does not have high specificity, and it is also taken up in infectious and inflammatory processes[19,20]. ¹⁸F-FDG uptake after several cycles of chemotherapy may occur due to the presence of a persisting viable tumor or as a result of local inflammation[21]. It is also possible that the immunotherapy increased inflammation around the lesion. Antibody-mediated cellular cytotoxicity and complement activation are important mechanisms of action of rituximab[22,23], and both of these processes can attract inflammatory mediators to the tumor site. The variable use of rituximab in a minority of patients in previous studies, compared with its use in all of the patients in our study, may explain the high rate of FDG positivity unrelated to tumor activity[7,24].

Given the hypothesis that an early change in the treatment plan may lead to a greater number of cures in DLBCL patients, a strategy of treatment based on PET/CT performed at various time points during treatment could improve survival. In the present study, 15 patients with positive PET/CT2 scans showed progression of the disease at PET/CT4. Among these 15 patients, 6 had their treatment plans changed, and 2 of them achieved CR and remained alive at 37 and 48 months’ follow-up. In the remaining 9 patients in whom the treatment plan was not altered according to the PET/CT4 findings, treatment was considered to have failed; all of these patients had died by the end of follow-up, with a median survival of 13 months. Although the number was small, some patients benefited from PET/CT-based treatment strategy. In our study, 36.8% (32/87) of the PET/CT2-positive patients showed progression of the disease during chemotherapy. Our results suggest that repeat PET/CT is needed if PET/CT findings are positive after 2 cycles of chemotherapy. Such a strategy would improve the management of patients with DLBCL, which we hope will translate into a longer survival time.

We acknowledge the limitations and potential biases of this study due to the retrospective collection of data and the relative disparity of the treatment types. In clinical practice, positive and negative criteria vary widely between individual nuclear medicine specialists, and only “negative” or “positive” was reported in this study; the hematologists did not know whether the patient’s disease had progressed and could not adjust the treatment plan according to the I-PET/CT findings. Although PET/CT is a promising technique, reproducible and universal interpretation criteria are required to enable reliable conclusions to be drawn.