Abstract
We retrospectively analyzed the prognosis of patients with diffuse large B cell lymphoma (DLBCL) and a bulky mass at diagnosis. We retrospectively analyzed clinical data for 29 consecutive DLBCL patients with an initial bulky mass receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy from 2004 to 2011. Bulky disease was defined as a measurable tumor mass >10 cm in diameter or a mediastinal mass >1/3 of the chest diameter. Patients with primary mediastinal large B-cell lymphoma were excluded. The median age was 65 years (20–78 years) and the maximum tumor diameter was 11.5 cm (10.0–17.0 cm). Complete response and partial response were achieved in 14 patients each, while 1 patient had progressive disease. The 3-year overall survival (OS) rate and progression-free survival (PFS) rate were 66 and 56 %, respectively. Findings on post-treatment positron emission tomography-computed tomography (PET–CT) were significantly associated with OS (34 % for patients with abnormal uptake vs. 75 % for those without, P = 0.014), and were also associated with PFS (36 vs. 83 %, respectively, P < 0.001). Nine patients with a single site of abnormal uptake on PET–CT underwent radiotherapy and 5 of them subsequently relapsed. An initial bulky mass does not indicate a poor prognosis of DLBCL. However, the post-treatment PET–CT findings may have predictive value in DLBCL patients with a bulky mass.
Keywords: Diffuse large B-cell lymphoma, Bulky mass, PET–CT
Introduction
In the pre-rituximab era, most (but not all) researchers reported that bulky disease had an influence on the outcome in patients with aggressive lymphoma and diffuse large B-cell lymphoma (DLBCL) [1–7]. Divergent results were obtained because of differences in the patient populations studied. After R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) became the standard treatment, the prognosis of DLBCL with a bulky mass was re-examined. The US Intergroup trial did not demonstrate that tumor size was an important indicator in DLBCL patients receiving R-CHOP therapy [8], and bulky disease (a mass ≥10 cm in diameter) was not identified as a prognostic factor in the Groupe d’Etude des Lymphomes de l’Adulte (GELA) Study [9]. However, a recent extrapolative analysis of the MabThera International Trial Group (MInT) study found a stronger influence of the maximum size of bulky masses on the outcome of patients in the rituximab era [10]. Thus, the influence of a bulky mass on the outcome of DLBCL patients receiving R-CHOP therapy is still unclear.
In patients with a bulky mass, residual tumor is often detected by CT at the end of treatment, and it is sometimes difficult to determine whether additional treatment such as radiotherapy should be performed or not. According to the NCCN guidelines (2013 ver. 1), if PET–CT is positive at the end of treatment for limited DLBCL with a bulky mass (>10 cm), radiotherapy should be considered (Category 1). In patients with advanced DLBCL and a bulky mass, however whether radiotherapy is required should be determined on a case-by-case basis (Category 2B).
In the present study, we retrospectively investigated the outcome of DLBCL patients with a bulky mass and also assessed the accuracy of predicting the prognosis based on the post-treatment PET–CT findings.
Materials and Methods
Bulky disease was defined as a measurable mass ≥10 cm diameter or a mediastinal mass >1/3 of the chest diameter [11]. If a bulky mediastinal mass showed invasion of the surrounding structures and was pathologically diagnosed as DLBCL, the patient was considered to have primary mediastinal large B-cell lymphoma and was excluded from this study. From February 2004 to July 2011, 201 consecutive patients who had untreated DLBCL received R-CHOP therapy (cyclophosphamide 750 mg/m2 on Day 1; doxorubicin 50 mg/m2 on Day 1; vincristine 1.4 mg/m2 on Day 1 (max 2 mg); prednisolone 60 mg/m2 on Days 1–5; and rituximab 375 mg/m2 on Day 15) for up to 6–8 cycles without weight loss [12]. Treatment was given in 21 day cycles. Among these 201 patients, 29 had a bulky mass. We compared treatment outcomes between the bulky mass group (n = 29) and the non-bulky mass group (n = 172). Stage I, II of Ann arbor classification limited-stage, Stage III, IV was defined as advanced stage. We also studied prognostic factors and the accuracy of predicting the outcome based on detection of residual disease at the end of R-CHOP therapy in the bulky mass group. The criteria of Cheson et al. were used to assess the effectiveness of treatment [13] Positron emission tomography-computed tomography (PET–CT) with 18-F-fluorodeoxyglucose performed before initiation of R-CHOP therapy and 6–8 weeks after the completion of R-CHOP therapy. A negative PET scan was defined as showing no abnormal uptake or minimal residual uptake. Mediastinal blood pool activity was used as the reference to define PET positivity. If a residual mass ≥2.0 cm in greatest transverse diameter (or a smaller residual mass or normal-sized lymph node) showed higher uptake than the blood pool, the PET scan was considered to be positive. All PET–CT scans were reviewed by a single nuclear medicine physician.
Overall survival (OS) was defined as the interval from diagnosis until death from any cause or the final date of observation. Progression-free survival (PFS) was defined as the interval from diagnosis until relapse or progression of lymphoma, death from any cause, or the final date of observation (if progression or death did not occur). Survival was calculated by the Kaplan–Meier method, and differences in survival were assessed by the log-rank test. The relative risk and its 95 % confidence interval (CI) were determined, as well as P values. All P values were two-sided, with significance being accepted at P ≤ 0.05. Statistical analyses were performed with R2.10.1 software (R Foundation for Statistical Computing, Vienna, Austria). This study was approved by the institutional review board of Kanagawa Cancer Center.
Results
Patient Profile
The median age of the patients with a bulky mass was 65 years (range 20–78 years). The most frequent site of a bulky mass at presentation was the mesenteric lymph nodes (55 %) and the maximum tumor diameter was 11.5 cm (10.0–17.0 cm). The characteristics of the 29 patients are presented in Table 1. The number of patients in stages I, II, III, and IV was 3, 10, 7, and 9, respectively. There were no significant differences of stage distribution between the two groups (P = 0.625). The International prognostic index (IPI) risk category was low, low-intermediate, high-intermediate, and high for 6, 10, 8, and 5 of the patients, respectively. Patients with a bulky were more likely to be in poor risk categories, though this was not statistically significant (P = 0.069). Patients with a bulky mass were significantly more likely to have a performance status (PS) ≥ 2 (45 vs. 19 %, P = 0.005), elevation of serum lactate dehydrogenase (LDH) (86 vs. 61 %, P = 0.007), and B symptoms (38 vs. 17 %, P = 0.017).
Table 1.
Patient characteristics (n = 201)
| Variables | DLBCL with a bulky mass (n = 29) | DLBCL without a bulky mass (n = 172) | P value | ||
|---|---|---|---|---|---|
| No. of patients | (%) | No. of patients | (%) | ||
| Median age (range) | 65 (20–78) | 64 (19–84) | 0.765 | ||
| Gender | |||||
| Male | 15 | 52 | 93 | 54 | 0.974 |
| Female | 14 | 48 | 79 | 46 | |
| Performance status | |||||
| 0–1 | 16 | 55 | 139 | 81 | 0.005 |
| ≧2 | 13 | 45 | 33 | 19 | |
| LDH | |||||
| Normal | 4 | 14 | 67 | 39 | 0.007 |
| Elevated | 25 | 86 | 105 | 61 | |
| Stage | |||||
| I | 3 | 10 | 29 | 17 | 0.625 |
| II | 10 | 34 | 60 | 35 | |
| III | 7 | 25 | 43 | 25 | |
| IV | 9 | 31 | 40 | 23 | |
| Extranodal lesion | |||||
| 0–1 | 20 | 69 | 119 | 69 | 0.847 |
| ≧2 | 9 | 31 | 53 | 31 | |
| Bone marrow involvement | |||||
| Yes | 4 | 14 | 15 | 8 | 0.602 |
| No | 25 | 86 | 157 | 92 | |
| B symptoms | |||||
| A | 18 | 62 | 143 | 83 | 0.017 |
| B | 11 | 38 | 29 | 17 | |
| International prognostic index | |||||
| Low risk | 8 | 28 | 72 | 42 | 0.069 |
| Low-intermediate risk | 5 | 17 | 39 | 23 | |
| High-intermediate risk | 6 | 21 | 31 | 18 | |
| High risk | 10 | 34 | 30 | 17 | |
DLBCL diffuse large B-cell lymphoma, LDH lactate dehydrogenase
Outcome of Patients with and Without a Bulky Mass
The median follow-up time for surviving patients was 3.2 years (range: 0.7–8.0 years). Figure 1 shows the 3-year OS and PFS of patients who had limited disease with or without a bulky mass. There were no significant differences between the two groups (90 % [95 % CI 84–98] vs. 69 % [95 % CI 45–100] [P = 0.105] and 83 % [95 % CI 75–92] vs. 77 % [95 % CI 57–100] [P = 0.499], respectively). Figure 2 shows the 3-year OS and PFS of patients who had advanced disease with or without a bulky mass. Again, there were no significant differences between the two groups (76 % [95 % CI 67–87] vs. 66 % [95 % CI 43–100] [P = 0.279] and 72 % [95 % CI 63–83] vs. 28 % [95 % CI 65–100] [P = 0.096], respectively).
Fig. 1.
Overall survival of all patients. a Limited disease. b Extensive disease
Fig. 2.
Progression-free survival of all patients. a Limited disease. b Extensive disease
Prognosis of Patients with a Bulky Mass
When prognostic factors for OS and PFS were assessed by univariate analysis, the findings on post-treatment PET–CT were statistically associated with OS (34 % [95 % CI 12–94] for PET-positive patients vs. 75 % [95 % CI 43–100] for PET-negative patients [P = 0.014]) and with PFS (36 % [95 % CI 18–72] vs. 83 % [95 % CI 58–100], respectively [P < 0.001]) (Fig. 3; Table 2). In contrast, the age, PS, LDH, stage, and extranodal disease were not significantly associated with either OS or PFS.
Fig. 3.
Overall survival and progression-free survival of patients with a bulky mass stratified by post-treatment PET–CT findings. a Overall survival. b Progression-free survival
Table 2.
Prognostic factors with a bulky mass (univariate analysis)
| Variables | No. of patients | 3-year OS | 3-year PFS | ||
|---|---|---|---|---|---|
| % | P value | % | P value | ||
| Age, years | |||||
| < 60 | 13 | 66 | 0.504 | 58 | 0.876 |
| ≥ 60 | 16 | 60 | 47 | ||
| Performance status | |||||
| 0–1 | 16 | 78 | 0.357 | 62 | 0.967 |
| ≥ 2 | 13 | 53 | 46 | ||
| Stage | |||||
| Limited stage | 13 | 83 | 0.388 | 77 | 0.163 |
| Extensive stage | 16 | 66 | 28 | ||
| LDH | |||||
| Normal | 4 | 100 | 0.096 | 100 | 0.101 |
| Elevated | 25 | 57 | 45 | ||
| International prognostic index | |||||
| Low, low-intermediate risk | 13 | 71 | 0.644 | 69 | 0.498 |
| High-intermediate, high risk | 16 | 62 | 41 | ||
| Post treatment PET–CT status | |||||
| Negative | 14 | 75 | 0.014 | 83 | <0.001 |
| Positive | 14 | 34 | 36 | ||
LDH lactate dehydrogenase, OS overall survival, PET–CT positron emission tomography-computed tomography, PFS progression-free survival
PET–CT was performed before treatment in 27 patients, but not in 2 patients with rapid disease progression. At the end of treatment, 28 patients underwent PET–CT, excluding 1 patient with disease progression, and 14 patients had no abnormal uptake of FDG. Although 5 (2 with limited disease and 3 with advanced disease) of the 14 patients still had residual tumors on CT, none of them received additional treatment (including radiation therapy) and all of them remained in remission at the end of the observation period. The other 14 patients had abnormal FDG uptake at the completion of R-CHOP therapy. Nine of these patients (3 with limited disease and 6 with advanced disease) still had a bulky mass on CT, and 5 of them developed recurrence after receiving radiotherapy.
Discussion
The presence or absence of a bulky mass is not included in the IPI, which is widely used for predicting the prognosis of DLBCL. However, a poor prognosis has been reported for DLBCL patients with large extranodal lesions or those with tumors more than 5.0–10.0 cm in diameter [10, 14, 15]. One problem is the lack of a generally accepted definition of a bulky mass. In the present study, we defined a bulky mass as a tumor ≥10 cm diameter or a mediastinal mass >1/3 of the chest diameter, according to the Cotswolds classification, which is widely used for clinical staging of malignant lymphoma. As a result, we found that DLBCL patients with a bulky mass tended to have features that were suggestive of progressive disease, including a worse PS, B symptoms, a higher serum LDH level, and a higher IPI risk than in the patients without a bulky mass. However, the presence of a bulky mass was not correlated with a poor prognosis among patients with either limited disease or advanced disease.
Among DLBCL patients with a bulky mass before treatment, regardless of whether or not a residual mass was detected by CT after R-CHOP therapy, those who were negative for abnormal uptake on PET–CT had a good prognosis without additional treatment, whereas those with abnormal uptake had a poor prognosis. According to Juweid et al., about half of the patients with DLBCL achieving PR on post-treatment CT showed no uptake of FDG, and their progression-free survival was almost equivalent to that of CR patients without additional treatment and was better than that of patients with FDG uptake [16]. There have been few reports about the outcome of DLBCL with a bulky mass based on post-treatment PET–CT findings. Our results suggested that performing PET–CT at the end of R-CHOP therapy may be useful for predicting the prognosis, similar to the case for DLBCL without a bulky mass. In contrast, stage, and IPI risk were not significantly associated with either OS or PFS. This analysis of small number of patient, it is considered one of the causes.
However, the positive predictive value of PET–CT is not so high, since judgment of positive uptake is difficult and poor reproducibility of assessment between interpreters has been pointed out. Although we used the efficacy criteria proposed by Cheson et al., a five-point scale has recently been employed in clinical trials with interim PET and the usefulness of this scale has been reported [17]. Therefore, the criteria for assessing efficacy should be studied further and standardization of the criteria for PET–CT positivity should be a target for the future.
Radiotherapy for residual lesions did not seem to be important in our patients who showed no uptake on post-treatment PET–CT at the end of R-CHOP therapy. However, the present study was not designed to assess the usefulness of radiotherapy, emphasizing the need for additional clinical studies.
In conclusion, the present study demonstrated that a bulky mass was not a poor prognostic indicator for patients with DLBCL. Instead, the results of PET–CT at the end of treatment may be useful for predicting the prognosis. Although our study had the limitations of a retrospective design and a small number of subjects, the results suggested that radiotherapy may not be required for a residual bulky mass if there is no abnormal FDG uptake on PET–CT at the end of R-CHOP therapy. However, confirmation by a prospective study is needed.
Acknowledgments
Conflict of interest
The authors have no conflict of interest to declare.
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