The role of 18F-FDG PET/CT in patients with diffuse large B-cell lymphoma after radioimmunotherapy using 131I-rituximab as consolidation therapy.

PURPOSE: To evaluate the prognostic value of pretreatment 18F-FDG PET/CT after consolidation therapy of 131I-rituximab in patients with diffuse large B-cell lymphoma (DLBCL) who had acquired complete remission after receiving chemotherapy.
METHODS: Patients who were diagnosed with DLBCL via histologic confirmation were retrospectively reviewed. All patients had achieved complete remission after 6 to 8 cycles of R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone) chemotherapy after which they underwent consolidation treatment with 131I-rituximab. 18F-FDG PET/CT scans were performed before R-CHOP for initial staging. The largest diameter of tumor, maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were obtained from pretreatment 18F-FDG PET/CT scans. Receiver-operating characteristic curves analysis was introduced for assessing the optimal criteria. Kaplan-Meier curve survival analysis was performed to evaluate both relapse free survival (RFS) and overall survival (OS).
RESULTS: A total of 15 patients (12 males and 3 females) with a mean age of 56 (range, 30-73) years were enrolled. The median follow-up period of these patients was 73 months (range, 11-108 months). Four (27%) patients relapsed. Of them, three died during follow-up. Median values of the largest tumor size, highest SUVmax, MTV, and TLG were 5.3 cm (range, 2.0-16.4 cm), 20.2 (range, 11.1-67.4), 231.51 (range, 15-38.34), and 1277.95 (range, 238.37-10341.04), respectively. Patients with SUVmax less than or equal to 16.9 showed significantly worse RFS than patients with SUVmax greater than 16.9 (5-year RFS rate: 60% vs. 100%, p = 0.008). Patients with SUVmax less than or equal to 16.9 showed significantly worse OS than patients with SUVmax greater than 16.9 (5-year OS rate: 80% vs. 100% p = 0.042).
CONCLUSION: Higher SUVmax at pretreatment 18F-FDG PET/CT was associated with better relapse free survival and overall survival in DLBCL patients after consolidation therapy with 131I-rituximab. However, because this study has a small number of patients, a phase 3 study with a larger number of patients is needed for clinical application in the future.

Introduction

Diffuse large B-cell lymphoma (DLBCL) is characterized by an aggressive phenotype. It is the most frequent type of non-Hodgkin lymphoma (NHL), accounting for 30–40% of all NHL cases [1, 2]. Over the last decade, the addition of rituximab to traditional cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy has led to significant advances and improvements inf treatment response and survival for patients with DLBCL [3, 4]. Despite therapeutic advances with the R-CHOP regimen, about 40% of patients with DLBCL cannot be completely cured with R-CHOP therapy. Owing to the high risk of treatment failure, many researchers have suggested consolidation therapy such as autologous stem cell transplantation (ASCT) [5]. However, many patients experience difficulties upon receiving ASCT due to advanced age or poor performance.

Radioimmunotherapy (RIT) is a treatment option that uses Ytrtrium-90 or Iodine-131 conjugated to anti-CD20 monoclonal antibodies to release high-energy, short distance radiation to tumor cells while avoiding damage to adjacent normal tissues. 90Y-ibritumomab (Zevalin, Spectrum Pharmaceuticals) is the only RIT currently approved in Europe, and its successful use in consolidation treatment following chemotherapy has been well documented in patients with follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL) [6, 7]. The use of 131I-tositumomab (Bexxar, GlaxoSmithKline) as a consolidation therapy has also been reported in CLL, advanced DLBCL, and FL [8-10]. Meanwhile, a study using rituximab as a consolidation therapy was conducted in a phase 2 clinical study at our institution [11]. This study is based on the rationale that RIT using 131I and Zevalin have a similar mechanism for targeting CD20 positive B-Cell lymphoma, but due to different physical and biological properties, a difference in survival rate was expected. In the phase 2 trial study, 131I-rituximab showed promising efficacy as consolidation treatment for patients with DLBCL.

Using functional imaging such as fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography (18F FDG PET) scan, an innovative approach for predicting outcomes of therapy for DLBCL has been developed. In 2007, the revised international Working Group response criteria for malignant lymphoma strongly suggested the use of PET for patients with FDG-avid, curable lymphomas like DLBLCL at 6–8 weeks after completion of therapy for evaluating complete response, for better delineating the extent of disease prior to treatment, and for obtaining the prognostic value of interim PET to predict the overall response to therapy and long-term outcomes [12, 13]. However, no studies have reported the prognostic ability of pretreatment 18F-FDG PET/CT using 131I-rituximab as a consolidation therapy in patients with DLBCL.

Thus, the aim of this study was to evaluate prognostic value of pretreatment 18F-FDG PET/CT using 131I-rituximab as a consolidation therapy in DLBCL patients who had acquired complete remission after receiving chemotherapy.

Materials and methods

Patient enrollment

We retrospectively reviewed a prospective, single-center phase 2 trial initiated in December 2004 and conducted at the Korea Cancer Center Hospital in the Republic of Korea (WHO-ICTRP ID: KCT0000526) [11]. Protocols of this study were approved by our Institutional Review Board (IRB No.: 2019-02-009), and the requirement to obtain informed consent was waived because this study is a retrospective study in which patients’ information is anonymized and this study might provide valuable knowledge to improve the patient care. We enrolled patients who were originally diagnosed with advanced stage (Ann Arbor III or IV) or bulky stage II DLBCL via histologic confirmation.

Inclusion criteria for our study were as follows: adequate performance status (Eastern Cooperative Oncology Group performance status of 0–2), hematology (absolute neutrophil count ≥ 1500/μL, hemoglobin level ≥ 8.0 g/dL, and platelet count ≥ 100,000/μL), and serum chemistries (serum transaminase level less than five times the upper limit of normal, serum total bilirubin level < 4 mg/dL, and a serum creatinine level < 1.5 mg/dL). Our exclusion criteria were as follows: primary central nervous system lymphoma or CNS involvement, recent (< 5 years) history of other malignancies, and hemodynamic instability due to recent (< 12 months) history of severe heart disease. The primary end point was relapse-free survival (RFS) and the secondary endpoint was overall survival (OS).

18F-FDG PET/CT scanning protocols

18F-FDG PET/CT scans were carried out before the R-CHOP for initial staging. All patients underwent fasting at least for 6 h before intravenous administration of 7.4 MBq/kg of 18F -FDG. The specific activity and radiochemical purity of 18F-FDG were > 37 GBq/μmol and > 98%, respectively. All patients had blood glucose levels checked routinely to ensure that they did not exceed 7.2 mmol/L. Whole-body PET acquisition from the skull base to the thighs started 60 minutes after the 18F-FDG injection.

Treatment protocols

Patients who received six or eight cycles of R-CHOP and showed complete response participated in this study. 131I-rituximab was used for consolidation therapy. It was administered within 8 weeks of the last administration of R-CHOP. Potassium iodide was also provided at least 24 h prior to 131I-rituximab administration for thyroid protection. Before the administration of unlabeled rituximab, patients received premedications of acetaminophen, diphenhydramine, and a serotonin antagonist. Next, 70 mg of unlabeled rituximab was injected to inhibit peripheral B cells. Then 131I-rituximab (200 mCi of 131I conjugated with 30 mg of rituximab) was administered less than 4 h after the administration of unlabeled rituximab. Iodination of rituximab was carried out with Iodo-Beads (Pierce Chemical Co, Rockford, IL, USA) in our radiochemical laboratory, using the method described previously [14]. The patient stayed in the hospital for 5 days. Potassium iodide was provided for 14 days.

Imaging analysis

Imaging interpretation was based on the consensus of two nuclear medicine physicians. The largest diameter of tumor was examined on axial images of CT for attenuation correction of the PET. Lymphoma involvement in CT images were matched with PET images side by side.

Standardized uptake value (SUV) was defined as the tissue concentration (MBq/mL) of the tracer divided by the amount injected per body weight (MBq/g). MIMvista workstation software version 6.8.3 (MIM Software Inc., Cleveland, OH, USA) was used for measuring the SUVmax, MTV, and TLG of lesions. Patient-based analysis was based on the highest SUVmax when multiple lesions were present. MTV was automatically obtained from the tumor volume combined with FDG uptake with a gradient-based method (PET edge) [15]. TLG was defined as MTV multiplied by SUVmean. The gradient method depends on the starting point at the center of the lesion determined by the operator. When the operator drags out from the lesion center, six axes spread out, providing visual feedback for the stating point. Spatial gradients were assessed along each axis. If a large spatial gradient was discovered, the length of an axis was limited [2, 16, 17].

Definition of relapse-free survival and overall survival

Relapse was based on imaging results and clinical data. Follow-up period was defined as the period from the date of RIT to the date of the last follow-up or death. Relapse-free survival (RFS) was defined as the time interval from the date of RIT to the date of the first documented recurrence or progression of disease. If there was no documented recurrence, RFS was calculated as the time interval from the date of RIT to the date of last follow-up or death. Overall survival (OS) was defined as the time interval from the date of RIT to the date of the last follow-up or death.

Statistical analysis

All statistical analyses were performed using the MedCalc software version 16.4.3 (MedCalc Software, Mariakerke, Belgium). Categorical variables are displayed as numbers and percentages. Continuous variables are presented as median values with a range. Five-year survival rates were calculated. We assessed the optimal criteria for the highest sum of sensitivity and specificity in terms of tumor size, SUVmax, MTV, and TLG using receiver operating characteristic (ROC) curve analysis. Kaplan-Meier curve survival analysis was used to assess both RFS and OS. A P-value of less than 0.05 was considered statistically significant.

Results

Patient characteristics

Clinical information of patient characteristics is presented in Table 1. Three (20%) patients were female. The median age was 56 years (range, 30–73 years). Three (20%) patients were diagnosed with bulky stage II disease. Four and eight patients were diagnosed with stage III and stage IV diseases, respectively. Extranodal involvement was found in eight (53%) patients. Regarding eastern cooperative oncology group (ECOG) performance status, 12 (80%) patients had a score of 1 and three (20%) patients had a score of 2.

Table 1

Clinical characteristics of patients.

Patient No.	Age (years)	Sex	Stage	extranodal involvement	IPI	Largest tumor size (cm)	Highest SUVmax	MTV	TLG	Location of highest SUVmax
1	48	M	2	0	1	9.4	34	264.42	6063.31	left cervical LN
2	56	F	4	2	4	6.4	11.1	911.34	2829.92	uterus
3	45	M	4	2	2	2.2	16.9	39.82	257.83	right supraclavicular LN
4	64	M	3	0	3	4.5	11.2	231.51	1277.95	both cervical LN
5	71	F	4	3	5	5.3	67.4	393.65	3714.19	abdominal LN
6	44	M	2	0	0	7.3	17.7	55.53	650.57	right cervical LN
7	30	M	4	6	3	16.4	24.8	765.55	10341.04	abdominopelvic LN
8	73	F	4	3	4	3.8	24.9	282.72	3343.07	left axilla LN
9	65	M	3	0	2	3.8	13.2	144.93	912.52	left supraclavicular LN
10	50	M	4	2	3	3.3	17.3	965.28	8366.97	left nasal cavity
11	51	M	3	0	1	2.0	20.2	78.98	772.03	left cervical LN
12	59	M	4	1	1	6.3	30.9	91.28	1002.01	sternum
13	67	M	2	0	2	7.2	13.4	169.09	907.2	bilateral cervical LN
14	64	M	3	0	2	3.0	21.3	38.34	238.37	right tonsil
15	53	M	4	1	1	9.7	26.1	430.65	4838.62	right common iliac LN

Treatment outcomes and follow-up results

Among the 15 patients who received consolidative 131I-rituximab, six achieved complete response (CR) after three cycles of R-CHOP and 9 achieved CR after six or eight cycles of R-CHOP. All 15 patients received consolidation RIT after achieving complete response. The median time from the day of the last R-CHOP administration to RIT was 48 days (range, 32–59 days). The median follow-up period of patients was 73 months (range, 11–108 months). Four (27%) patients relapsed. Of them, three died during follow-up. In one patient, follow-up magnetic resonance imaging showed brain metastasis 2 months after the administration of 131I-rituximab, and the patient died 9 months later due to disease progression. Another patient had a relapse of the disease 31 months later, and survived for 34 months before he died of disease progression. The last patient survived for 43 months after treatment. A graph of the survival period of all patients is shown in Fig 1.

Fig 1

A swimmer plot showing the survival period of 15 people.

Four people relapsed, of whom three expired. Those who relapsed are indicated by a red triangle, and those who survived are indicated by a black arrow.

Imaging findings

All patients underwent baseline 18F-FDG PET/CT before receiving R-CHOP treatment. A total of 50 lymph nodes of Ann Arbor classification in 15 patients showed positive FDG findings suggestive of lymphoma. The location was as follows: 10 in cervical and supraclavicular LN; 9 in Waldeyer’s ring; 7 in axillary and iliac LN each; 5 in aortic LN; 4 in mediastinal LN; 2 in brachial, mesenteric, inguinal LN and spleen each.

The median largest tumor size was 5.3 cm (range, 2.0–16.4 cm). The distribution of the location of the largest tumor was as follows: supraclavicular LN, 4 patients; axillary LN, 3; neck and mesentery, 2 each; abdomen LN, liver, L-spine and sigmoid colon, 1 each. The median highest SUVmax was 20.2 (range, 11.1–67.4). The distribution of the location of the highest SUVmax was as follows: cervical LN, 5 patients; abdominal LN and supraclavicular LN, 2 each; common iliac LN, axillary LN, uterus, nasal cavity, tonsil and sternum, 1 each. MTV and TLG were also measured with a gradient-based PET segmentation method (PET edge). Median values of MTV and TLG were 231.51 (range, 15–38.34) and 1277.95 (range, 238.37–10341.04), respectively.

ROC curve analysis

To obtain the cutoff values for survival analysis, ROC analysis was performed using the two endpoints of patient relapse and death. Regarding the detection for relapse of patients, the area under the curve (AUC)s of lesion size, SUVmax, MTV, and TLG were 0.670 (95% CI: 0.387 to 0.884), 0.977 (95% CI: 0.745 to 1.000), 0.545 (95% CI: 0.276 to 0.797), and 0.659 (95% CI: 0.377 to 0.877), respectively. Only SUVmax was found to be statistically significant (p < 0.001). The optimal cutoff values for lesion size, SUVmax, MTV, TLG were 6.4, 16.9, 231.51, 2829.92 with sensitivity/specificity of 100%/45%, 100%/91%, 75%/55%, and 100%/55%, respectively.

For discriminating the death of patients, AUCs of lesion size, SUVmax, MTV, and TLG were 0.639 (95% CI: 0.358 to 0.863), 0.944 (95% CI: 0.696 to 0.999), 0.500 (95% CI: 0.239 to 0.761), and 0.639 (95% CI: 0.358 to 0.863), respectively. Only SUVmax was found to be statistically significant (p < 0.001). The optimal cutoff values for lesion size, SUVmax, MTV, and TLG were 6.4, 16.9, 39.82, and 2829.92 with sensitivity/specificity of 100%/42%, 100%/83%, 67%/8%, and 100%/50%, respectively.

Survival analysis

Details of patients’ RFS are shown in Table 2 and Fig 2. Median RFS time was 73 months (range, 2–108 months). Two-year and five-year RFS rates were 93% and 86%, respectively. Regarding RFS, only the SUVmax showed a statistically significant difference. Patients with SUVmax less than or equal to 16.9 (n = 5) showed significantly worse RFS than patients with SUVmax greater than 16.9 (n = 10) (Fig 2b; p = 0.008, by a log-rank test). Two-year/five-year RFS rates were 80%/60%, for patients with SUVmax less than or equal to 16.9 and 100%/100% for patients with SUVmax greater than 16.9. Tumor size parameter also showed a difference in survival. However, such difference was not statistically significant. Patients with tumor size less than or equal to 6.4 cm (n = 10) showed worse RFS than patients with tumor size greater than 6.4 cm (n = 5) (Fig 2a; p = 0.051 by a log-rank test). Two-year/five-year RFS rates were 75%/50% for patients with tumor size less than or equal to 6.4 cm and 100%/100% for patients with tumor size greater than 6.4 cm.

Table 2

Results of univariate Kaplan-Meier survival analysis for relapse free survival.

Variable	n	5-year survival rate	P-value
Median age			0.234
<56 years	7 (47)	86%
≥56 years	8 (53)	88%
Sex			0.133
Male	12 (80)	92%
Female	3 (20)	67%
Ann Arbor stage			0.499
Stage 2 (bulky)	3 (20)	100%
Stage 3	4 (27)	100%
Stage 4	8 (53)	73%
IPI			0.176
Low risk (0–1)	5 (33)	100%
Intermediate risk (2–3)	7 (47)	86%
High risk (4–5)	3 (20)	67%
ECOG performance status			0.940
0	0 (0)	not applicable
1	12 (80)	91%
2	3 (20)	67%
Largest tumor size (cm)			0.051
≤6.4	10 (67)	79%
>6.4	5 (33)	100%
Baseline SUVmax			0.008
≤16.9	5 (33)	60%
>16.9	10 (67)	100%
Baseline MTV (mL)			0.646
≤231.51	8 (53)	88%
>231.51	7 (47)	86%
Baseline TLG			0.146
≤2829.92	9 (60)	78%
>2829.92	6 (40)	100%

*Numbers in parentheses are percentages.

SUVmax, the maximum standardized uptake value; MTV, metabolic tumor volume; TLG, total lesion glycolysis

Fig 2

Kaplan-Meier survival curves depicting relapse-free survival (RFS) according to tumor size (a), the maximum standardized uptake value (SUVmax) (b), metabolic tumor volume (MTV) (c), and total lesion glycolysis (TLG) (d).

Details of patients’ OS are shown in Table 3 and Fig 3. Median OS time was 73 months (range, 11–108 months). Two-year and five-year OS rates were 93% and 93%, respectively. Female patients (n = 3) showed significantly worse OS than male patients (n = 12) (Table 3; p = 0.046 by log-rank test). Two-year/five-year OS rates were 67%/67% for female patients and 100%/100% for male patients. Only the SUVmax showed statistically significant difference. Patients with SUVmax less than or equal to 16.9 (n = 5) showed significantly worse OS than patients with SUVmax greater than 16.9 (n = 10) (Fig 3b; p = 0.042, by a log-rank test). Two-year/five-year OS rates were 80%/80% for patients with SUVmax less than or equal to 16.9 and 100%/100% for patients with SUVmax greater than 16.9.

Table 3

Results of univariate Kaplan-Meier survival analysis for overall survival.

Variable	n	5-year survival rate	P-value
Median age			0.545
<56 years	7 (47)	100%
≥56 years	8 (53)	88%
Sex			0.046
Male	12 (80)	100%
Female	3 (20)	67%
Ann Arbor stage			0.548
Stage 2 (bulky)	3 (20)	100%
Stage 3	4 (27)	100%
Stage 4	8 (53)	88%
IPI			0.102
Low risk (0–1)	5 (33)	100%
Intermediate risk (2–3)	7 (47)	86%
High risk (4–5)	3 (20)	67%
ECOG performance status			0.511
0	0 (0)	not applicable
1	12 (80)	100%
2	3 (20)	67%
Largest tumor size (cm)			0.162
≤6.4	10 (67)	90%
>6.4	5 (33)	100%
Baseline SUVmax			0.042
≤16.9	3 (20)	80%
>16.9	12 (80)	100%
Baseline MTV			0.103
≤39.82	2 (13)	100%
>39.82	13 (87)	92%
Baseline TLG			0.26
≤2829.92	9 (60)	89%
>2829.92	6 (40)	100%

*Numbers in parentheses are percentages.

SUVmax, the maximum standardized uptake value; MTV, metabolic tumor volume; TLG, total lesion glycolysis

Fig 3

Kaplan-Meier survival curves depicting overall survival (OS) according to tumor size (a), the maximum standardized uptake value (SUVmax) (b), metabolic tumor volume (MTV) (c), and total lesion glycolysis (TLG) (d).

Case description

Two representative cases demonstrate the relationship between SUVmax from pretreatment 18F-FDG PET/CT and prognosis. A 45-year-old male was diagnosed with DLBCL. He underwent baseline 18F-FDG PET/CT before receiving R-CHOP (Fig 4). The largest tumor size was measured to be 2.2 cm in the right supraclavicular LN. The highest SUVmax was 16.9 for the right supraclavicular LN. The patient reached complete remission after six cycles of R-CHOP. Following consolidation RIT, the patient relapsed with secondary hematologic malignancy at 31 months during 65 months of follow-up. He received all-transretinoic acid (ATRA) regimen for additional chemotherapy until he expired.

Fig 4

Lower maximum standardized uptake values (SUVmax) and poor prognosis after radioimmunotherapy (RIT) in a 45-year-old male patient diagnosed with diffuse large B-cell lymphoma (DLBCL).

The patient was at stage 4 with eastern cooperative oncology group (ECOG) performance status of 1, two extranodal involvement, and an intermediate risk of International prognostic index (IPI) score. 18F-FDG PET/CT showed disseminated hypermetabolic lymph nodes in tonsil, both submandibular, right supraclavicular, both axilla, both inguinal, both arm, and spleen. The largest tumor size was 2.2 cm. The highest SUVmax was 16.9 in the right supraclavicular LN. Metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were 39.82 and 257.83, respectively. The patient experienced recurrence at 31 months after RIT.

In contrast, a 71-year-old female underwent baseline 18F-FDG PET/CT after diagnosis with DLBCL (Fig 5). The largest lymphoma size was 5.3 cm with the highest SUVmax of 67.5 for the abdominal LN. The patient reached complete remission after 8 cycles of R-CHOP. Following consolidation RIT, the patient did not relapse during 56 months of follow-up.

Fig 5

Higher maximum standardized uptake values (SUVmax) and good prognosis after radioimmunotherapy (RIT) in a 71-year-old female patient diagnosed with diffuse large B-cell lymphoma (DLBCL).

The patient was at stage 4 with eastern cooperative oncology group (ECOG) performance status of 2, three extranodal involvement, and a high risk of international prognostic index (IPI) score. 18F-FDG PET/CT showed conglomerated hypermetabolic lymph nodes in tonsil, lateral neck, axillary chain, mediastinum, abdominopelvic, liver, and spleen. The largest lymphoma size was 5.3 cm on abdominal LN. The highest SUVmax was 67.4. Metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were 231.51 and 1277.95, respectively. The patient was followed up for 56 months without relapse.

Discussion

The present study demonstrates that pretreatment 18F-FDG-PET/CT can be used for predicting survival in DLBCL patients after consolidation therapy with 131I-rituximab. DLBCL patients with higher SUVmax of baseline 18F-FDG PET/CT showed better relapse free survival and overall survival after consolidation therapy with 131I-rituximab. To the best of our knowledge, this is the first study investigating the prognostic value of baseline 18F-FDG PET/CT in consolidation therapy using radioimmunotherapy. Results of this study confirmed that we could perform early classification of patients based on the risk of recurrence after consolidation therapy with 131I-rituximab. This would allow us to optimize the treatment administered to patients. For example, we could improve patient care by applying a more aggressive therapy for high-risk patients.

Previous studies have predicted the prognosis of patients with DLBCL and reported that it is valuable to employ interim PET and the end of treatment PET for predicting the prognosis of patients with DLBCL. Regarding interim PET, many researchers have found that interim PET can play an important role in predicting prognosis [18-23]. However, they applied different parameters, including changes in SUVmax, interim SUVmax [22], tumor to liver ratio [19], and a combination of Deauville Score and International Prognostic Index [20]. With respect to end of treatment PET, many studies have also elucidated that end of treatment PET provides a prognostic value for patients with DLBCL [19, 20, 24]. However, it is not easy to apply them for predicting prognosis after consolidation therapy of DLBCL because most patients tend to show complete remission, making it difficult to classify these patients. Therefore, baseline PET might be a better candidate to differentiate the prognosis of patients. Many studies have pointed out that baseline PET shows prognostic implication in patients with DLBCL [22, 25–34]. When utilizing baseline PET, many parameters such as SUVmax, sum of SUVmax, and MTV can be used for analysis.

In our study, it was found that a high SUVmax showed better treatment effect in DLBCL patients who received RIT consolidation therapy. Although, there are not many studies examining the prognostic factors of PET/CT in DLBCL patients who received RIT consolidation therapy after conventional chemotherapy, we compared our results with a study that investigated prognostic factors in patients who had not undergone consolidation therapy. In one meta-analysis, SUVmax and MTV were significant prognostic factors for progression free survival (PFS), but only MTV was reported as a significant factor for OS [35]. Also, in a review study of 20 studies, SUVmax showed significant predictive ability for PFS and OS in 5 studies compared to 17 out of 19 for MTV and 10 out of 13 for TLG showing significant predictive ability for both PFS and OS [36]. A recent study reported that SUVmax was either undetermined or was a prognostic factor only in PFS [37, 38].

To optimize the efficacy of baseline PET, many studies have used metabolic tumor volume [27-34]. These studies showed that higher MTV was associated with worse prognosis of PFS and OS. Similarly, our study revealed that higher MTV tended to be associated with worse prognosis of PFS and OS, although such associations were not statistically significant. In the case of MTV, several issues need to be resolved before MTV can be used as a predictor of prognosis. Until now, there is no standardized methodology for measuring MTV. When it comes to MTV threshold, some researchers employ absolute values such as 2.5 and 3.0, whereas other researchers utilize relative values such as 42%.

Regarding the mechanism of prediction, Gallicchio et al. have demonstrated better survival for patients with DLBCL having higher values of SUVmax who underwent 18F-FDG PET/CT imaging before receiving chemotherapy [25] (p = 0.0002, HR: 0.13, 95% CI: 0.04–0.46). The present study showed similar results, which was expected because higher level of glycolytic activity was associated with better response to chemotherapy. Furthermore, patients with large decline of SUVmax in post-treatment PET also have good prognosis in some types of carcinoma [39-41]. This suggests that higher SUV in pretreatment PET may predict better prognosis with good response to treatment. The prognostic value of 18F-FDG PET/CT in lymphoma has been established [42]. The uptake of 18F-FDG PET/CT in lymphoma is influenced diversely by multifactorial process of various biological factors such as oncogene expression, apoptosis and viable cell fraction, impacts of hypoxia, extent of inflammatory cell infiltration, and tumor location (nodal/extranodal) [43]. This can lead to uptake heterogeneity in patients with the same histologic subtype [42].

There are some mechanisms that can explain our results. Low SUVs could be associated with hypoxic tumors that can be less aggressive if not treated, but paradoxically more resistant to chemotherapy treatment [44]. Another possible explanation is that those with higher cell proliferation have higher SUV values [45], and those are more likely to respond to treatment [39, 46]. In vitro studies have revealed that cells resistant to chemotherapy show decreased FDG uptake, suggesting that altered glucose transporter may transport into resistant tumor cells [47, 48].

A few studies have examined the prognosis using 131I-rituximab as RIT with 18F-FDG PET/CT. Similar to our study, Lim et al. have investigated survival factors using 18F-FDG PET/CT for the treatment of lymphoma patients with 131I-rituximab [49]. Their results showed that SUVmax and tumor size were significant predictors. High SUVmax in pretreatment scan was related to poorer overall survival and progression-free survival. They also showed that greater tumor size was associated with poorer OS. However, their study included non-Hodgkin lymphoma patients who were refractory to therapy and patients with low grade lymphoma as well as patients with DLBCL, while our study was limited to DLBCL patients who showed complete remission after R-CHOP therapy. Thus, the different outcomes of the two studies could be the result of the differences in study design. Other studies have investigated prognosis using various types of radionuclides with 18F-FDG PET/CT [39, 50–52]. Among them, Cazaentre et al. used Y-90 ibritumomab tuixetan and Y-90 epratuzumab tetraxetan as RIT. Their results demonstrated that low SUVmax and low TLG values were associated with good response rates in both groups. However, their study also included other types of NHL patients such as those with mantle cell lymphoma and follicular lymphoma.

The present study has the following limitations. First, only small number of patients were recruited due to low enrollment. This was because the study had a difficulty with enrolling patients for consolidation therapy after complete remission had occurred. Second, non-randomization of the study limits the interpretation of its results. Only patients who received RIT consolidation therapy were included and not the ones who only received chemotherapy. Third, only pretreatment images were obtained. Tumor response could not be evaluated because only patients with CR were enrolled. Fourth, this study has limitations as it is a retrospective study, though data were collected prospectively. Despite these limitations, we consider it important to report our findings in the article in view of the prognostic value of 18F-FDG PET/CT in RIT consolidation therapy for DLBCL patients.

In conclusion, our result showed higher SUVmax at pretreatment 18F-FDG PET/CT was associated with better relapse free survival and overall survival in DLBCL patients who received consolidation therapy with 131I-rituximab. However, since the study was conducted with a small number of subjects and was limited to consolidation therapy patients, a phase 3 trial studies with a larger number of patients are needed before clinical application.

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We look forward to receiving your revised manuscript.

Kind regards,

Domenico Albano

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: No

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have restrospectively analyzed a prosepctive study of the usefulness of baseline PET/CT in DLBCL patients recieving RCHOP Chemotherapy and Bexxar consolidation therapy.

The manuscript is well-written, and results have been analyzed well.

A few minor points to be addressed:

1. page 14, line 124-125: potassium ioidide was also provided at least 24 hr~. I think the authors should add "for thyroid protection", as some readers may not be familiar with I-131 rituximab treatment protocol.

2. I am not familiar with I-131 rituximab being administered as consolidation therapy. Although it is not possible to compare with other patients who achieved complete remission and did not recieve I-131 rituximab, I think the authors should add a short discription on the possible advantages or reported advantages of this treatment protocol.

Reviewer #2: Choi et al present the results of a ?phase I trial of 131I rituximab as a consolidation therapy following standard of care treatment with 6-8 cycles of RCHOP chemotherapy. The authors report the results of 15 patients (12 males, 3 females) treated with 131I rituximab. The authors conclude that higher pretreatment SUV max predicts better relapse free survival and overall survival following consolidation therapy with 131I rituximab.

The paper has major concerns which would need to be addressed.

1. The details of the study are not sufficient. Was this a phase I study? What was the rationale for the study? Consolidation for DLBCL is not standard of care? How were patients selected and why? What were the intended benefits? What ethical approval was obtained and what is the clinical trial number? More details on trials/proposed consolidation therapy need to be included.

2. In the treatment outcomes and follow up section it mentions three patients died during follow up? What did they did of? Progressive disease or another reason? (line 186)

3. Two case descriptions are given (lines 259-291). Whilst interesting this is not a standard way to report outcomes in clinical trial. A swimmers plot including all patients enrolled with details about outcomes (relapse/death etc) would be more appropriate.

4. I do not agree with the conclusions or they are not explained adequately. The authors conclude that PET/CT pretreatment can be used to predict survival in DLBCL in patients receiving consolidation therapy. Does pretreatment PET/CT not predict outcomes for all patients regardless of whether they received consolidation therapy or not? It would be useful to know the impact of SUVmax pretreatment on survival outcomes of those who don't receive consolidation therapy (either from the literature or comparator cohort from the same institution). The authors conclude that the sex of the patient is associated with prognosis yet there are only 3 females in the cohort! These numbers and the skewed sex ratio of the cohort make it impossible to make any associations between sex and outcomes.

5. The limitations section needs to be significantly expanded and rewirtten. The context of the study is not clear and the list of limitations is long.

Overall the standard of English needs to be significantly improved, particularly the discussion section.

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

8 Jul 2022

Dear Dr. Chenette:

I thank the editors and referees of the ‘Plos One’ for taking their time to review my article.

I have made some corrections and clarifications in the manuscript after going over the referee’s comments. And I made a point-by-point reply to reviewer’s comments.

I have also checked the all PLOS ONE's style requirements. I have uploaded the minimal data set that fully anonymize all patient record.

I have specified the informed consent that was waived in the materials and methods section.

I hope the revised manuscript will better meet the requirements of the ‘Plos One’ for publication. I thank you again for the constructive review by the referees.

Sincerely,

Ilhan Lim, M.D., Ph.D.

Department of Nuclear Medicine, Korea Cancer Centre Hospital, Korea Institute of Radiological and Medical Sciences (KIRAMS), 75 Nowon-ro, Nowon-gu, Seoul, Korea

Tel: 82-2-970-1273; Fax: 82-2-970-2438; E-mail: ilhan@kcch.re.kr

Hye Jin Kang, M.D., Ph.D.

Division of Hematology and Medical Oncology, Department of Internal Medicine, Korea Institute of Radiological and Medical Sciences (KIRAMS), 75 Nowon-ro, Nowon-gu, Seoul, Korea

Tel: 82-2-970-1289; E-mail: hyejin@kirams.re.kr

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

19 Jul 2022

Please submit your revised manuscript by Sep 02 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Domenico Albano

Academic Editor

PLOS ONE

Additional Editor Comments :

The are some doubts about ethical conditions of this study, as reviewer 2 written.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have sufficently addressed to my questions.

The authors have elaborated on I-131 rituximab for consolidation in the introduction.

Reviewer #2: The authors have made substantial improvement to the manuscript. However I still have some major concerns. These mainly relate to how the study was conducted. In particular the sentence that states 'the requirement for informed consent was waived'. I cannot understand how a prospective trial of an investigational medicinal product could be conducted without informed consent from the participants. This goes against the Declaration of Helsinki and needs to be clarified before this manuscript can be considered for publication. In addition the standard of English is still poor and needs to be improved.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

1 Aug 2022

We would like to resubmit this manuscript [PONE-D-22-14199R1] - [EMID:3c112168cfebaa1e], entitled “The role of 18F-FDG PET/CT in patients with diffuse large B-cell lymphoma after radioimmunotherapy using 131I-rituximab as consolidation therapy” to PLOS ONE for publication. We appreciate the careful reviews provided by the editor and reviewers. We are submitting a revised version of our manuscript in which we have considered or responded to all of the comments and questions. Our detailed responses are given below. We have also replied to the reviewers’ comments in a point-by-point manner, and the changes made have been highlighted in red in the revised manuscript.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

8 Aug 2022

The role of 18F-FDG PET/CT in patients with diffuse large B-cell lymphoma after radioimmunotherapy Dear Dr. Lim Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised./>==============================

Please submit your revised manuscript by Sep 22 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

9 Aug 2022

We would like to resubmit this manuscript [PONE-D-22-14199R2] - [EMID:bb003148bf32d220], entitled “The role of 18F-FDG PET/CT in patients with diffuse large B-cell lymphoma after radioimmunotherapy using 131I-rituximab as consolidation therapy” to PLOS ONE for publication. We appreciate the careful reviews provided by the editor and reviewers. We are submitting a revised version of our manuscript in which we have considered or responded to all of the comments and questions. Our detailed responses are given below. We have also replied to the reviewers’ comments in a point-by-point manner, and the changes made have been highlighted in red in the revised manuscript.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

17 Aug 2022

The role of 18F-FDG PET/CT in patients with diffuse large B-cell lymphoma after radioimmunotherapy using 131I-rituximab as consolidation therapy

PONE-D-22-14199R3

Dear Dr. Lim,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Domenico Albano

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

16 Sep 2022

PONE-D-22-14199R3

The role of 18F-FDG PET/CT in patients with diffuse large B-cell lymphoma after radioimmunotherapy using 131I-rituximab as consolidation therapy

Dear Dr. Lim:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Domenico Albano

Academic Editor

PLOS ONE