Single Institutional Experience in the Treatment of Primary Mediastinal B Cell Lymphoma Treated with Immunochemotherapy in the Setting of Response Assessment by ¹⁸Fluorodeoxyglucose Positron Emission Tomography

Abstract

Purpose

Excellent outcomes obtained after infusional dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (R-EPOCH) alone have led some to question the role of consolidative radiation (RT) in the treatment of primary mediastinal B cell lymphoma (PMBL). We reviewed outcomes of patients treated with one of three rituximab-containing regimens (cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP]; hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone [R-HCVAD], or R-EPOCH) with or without RT, as well as the ability of positron emission tomography-computed tomography (PET-CT) to identify patients at risk of relapse.

Materials/Methods

We retrospectively identified 97 patients diagnosed with stage I/II PMBCL treated at our institution between 2001–2013. Clinical characteristics, treatment outcomes and toxicity were assessed. We analyzed whether post-chemotherapy PET-CT could identify patients at risk for progressive disease according to 5 point scale (5PS) Deauville score assigned. Among 97 patients (median follow-up time 57 months), the 5-year overall survival rate was 99%. Of patients treated with R-CHOP, 99% received RT; R-HCVAD, 82%; and R-EPOCH, 36%. Of 68 patients with evaluable end-of-chemotherapy PET-CT scans, 62% had a positive scan (avidity above that of the mediastinal blood pool [Deauville 5-point scale {5PS} =3]), but only 9 patients experienced relapse (n=1) or progressive disease (n=8), all with a 5PS of 4-5. Of the 25 patients who received R-EPOCH, 4 experienced progression, all with 5PS of 4-5; salvage therapy (RT and autologous stem cell transplant) was successful in all cases.

Conclusion

Combined modality immunochemotherapy and radiation is well tolerated and effective for treatment of PMBCL. A post-chemotherapy 5PS of 4-5, rather than 3-5, can identify patients at high risk of progression who should be considered for therapy beyond chemotherapy alone after R-EPOCH.

Introduction

Primary mediastinal B cell lymphoma (PMBL) is a distinct clinicopathologic entity characterized by a large mediastinal mass, a locally aggressive presentation, and a predilection for young women in their 4^th decade.^1,2 Originally described in the 1980s and later shown to account for roughly 2% of all non-Hodgkin lymphomas, PMBL is thought to originate from a thymic medullary B cell. Tumor cells express B-cell-associated antigens but share some features with nodular sclerosis Hodgkin lymphoma, including CD30 staining in >80% of cases and pleomorphic tumor cells with occasional Reed-Sternberg-like features and a gene expression pattern that shares about one third of genes with nodular sclerosis Hodgkin lymphoma.^3–7 Bulky disease larger than 10 cm is not uncommon, often with extramediastinal extension into the adjacent chest wall, lung and pericardium with pleural and cardiac effusions; however, distant disease at diagnosis is uncommon.^8,9 Relapses, on the other hand, tend to involve distant extranodal sites including the liver, kidneys, adrenal glands, GI tract, ovaries, pancreas and central nervous system.^10–12

Initial therapy for patients with PMBL includes anthracycline-based chemotherapy, the outcomes of which have been improved by the addition of CD20-targeted therapy.^13–16 Given the aggressiveness, tumor burden and bulk associated with this disease, consolidative radiation therapy (RT) has historically been considered a key component of therapy. Several retrospective studies have highlighted the role of RT in converting partial responses to complete responses and in maintaining local control in patients with complete responses to upfront chemotherapy.^{13,14,17–19} Most recently, however, the role of RT has been challenged because of the excellent outcomes reported in a small series from the National Cancer Institute (NCI) in which 51 patients with PMBL were treated with rituximab, vincristine, and prednisone in combination with dose-adjusted etoposide, doxorubicin and cyclophosphamide (R-EPOCH) in a single-arm prospective phase II study.²⁰ Use of this regimen, coupled with serial imaging with ¹⁸fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET-CT), revealed a 5-year event free survival (EFS) rate of 93%. Three patients had persistent or progressive disease identified by PET-CT after R-EPOCH; two received salvage RT and the third excisional biopsy. The overall survival rate in this small group was 97%; one patient died from treatment-related acute myeloid leukemia.

Interest has been increasing in defining whether post-immunochemotherapy PET-CT can be valuable for guiding subsequent treatment decisions for patients with PMBL, especially when mediastinal RT is being considered. A 5-point scale for defining PET-CT positivity has proven robust for patients with Hodgkin’s lymphoma, with uptake exceeding that of the mediastinal blood pool (MBP) suggesting the possibility of residual disease.²¹ In the largest prospective study of PET-CT in PMBL done to date, the International Extranodal Lymphoma Study Group (IELSG) obtained and centrally reviewed PET-CT scans from 115 patients after immunochemotherapy.²² In that group, 53% of patients had uptake greater than the MBP after immunochemotherapy, but outcomes were nevertheless excellent, with a 5-year overall survival (OS) rate of 92%. However, RT was generally given universally in that study, and it is unclear whether the RT contributed to the superior OS and progression-free survival (PFS) rates, particularly in light of the significant proportion of patients with positive scan findings after initial immunochemotherapy. In a recent retrospective study from the University of Bologna in which post-immunochemotherapy PET-CT was used to assign patients to undergo RT or observation, the disease-free survival rates at 10 years were equivalent between groups (90.7% and 90%, P=0.85),²³ suggesting that (a) RT may have a role as salvage therapy for persistent disease after systemic therapy and (b) PET-CT may have a role in identifying patients who do not require additional treatment after induction immunochemotherapy.

To address these open questions, we retrospectively reviewed outcomes of patients with stage I/II PMBL diagnosed and treated at our institution between 2001 and 2013 with one of three main rituximab-containing regimens: rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP); rituximab, fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (R-HCVAD); or R-EPOCH. The two goals of this study were twofold: to evaluate the outcome of patients treated with and without thoracic RT, and to evaluate the ability of PET-CT to identify patients at risk for local relapse.

Methods

After appropriate institutional board review approval, we retrospectively identified patients with newly diagnosed, Ann Arbor stage I–II PMBL that had been histologically confirmed and treated with rituximab-based treatment at our institution between 2001 and 2013. Patients who had been referred for evaluation or treatment of relapsed disease after initial therapy elsewhere were excluded. Patients who had received primary systemic therapy with appropriate follow-up imaging but had had RT elsewhere were included if details of the RT (such as dose, target and modality) could be obtained. Patients with pleural effusion were considered to have limited-stage disease unless pathologic confirmation of effusion involvement was obtained. Bulky disease was defined as disease that was >10 cm in axial diameter. The International Prognostic Index (IPI) was determined for all patients based on age (over or under 60 years), ECOG performance status (≤1 versus ≥2), serum lactate dehydrogenase (LDH) level (normal versus elevated), number of extranodal sites (≤1 versus >1) and disease stage (I/II versus III/IV).

Chemotherapy

All patients had been treated with rituximab-containing regimens. Most patients received R-CHOP, R-HCVAD, or R-EPOCH. The 8 patients who received a mixed regimen were grouped according to either the regimen given for the greatest number of cycles, or, if the number of cycles was equivalent (e.g., 3+3), the most aggressive regimen (with R-CHOP considered the least aggressive and R-EPOCH and R-HCVAD considered equivalent).

Imaging Assessment

CT scans with contrast were obtained from all patients before and after immunochemotherapy. Functional imaging was done 3–6 weeks after completion of systemic therapy. Gallium scanning was used for post-immunochemotherapy functional imaging before 2002, and PET or PET-CT was used afterward. In most cases, when the post-immunochemotherapy PET-CT scan showed evidence of uptake, additional PET-CT scans were obtained, either after RT (when radiation was given) or serially after immunochemotherapy for patients who did not receive RT.

Two experts in the interpretation of PET-CT scans (one nuclear medicine physician and one radiologist) independently reviewed the post-immunochemotherapy and post-radiation PET-CT scans while blinded to the identity of the patient. Response assessment was based on a 5-point scoring system (5PS, also known as the Deauville criteria), initially defined at a consensus conference in Deauville, France in 2009 and subsequently updated.^24,25 The 5PS defines FDG uptake relative to FDG in the mediastinal and liver blood pools as follows: (1) no uptake; (2) uptake greater than or equal to that in the mediastinum; (3) uptake greater than that in the mediastinum but less than or equal to that in the liver; (4) uptake moderately higher than that in the liver; and (5) uptake markedly increased compared with the liver; new sites of disease; or both.

According to the revised Lugano classification for response assessment in non-Hodgkin lymphoma published in 2014, patients with a 5PS score of 1-2 with or without a residual mass are considered to have a complete response.²⁶ Partial response is defined as a 5PS score of 4-5 with a residual mass of any size. Stable disease is defined as stable FDG avidity with a score of 4-5, and progressive disease is defined as a 5PS of 4-5 with an increase in intensity of uptake from baseline, with or without new avid lesions. The response of patients with a 5PS score of 3 is now considered ambiguous, and interpretation of this finding is based on the timing of assessment, the treatment, and the clinical context.²⁶ In previous definitions of response assessment by the International Harmonization Project in Lymphoma, a positive scan was defined as persistent uptake in a residual mass that was above that of the mediastinal blood pool (i.e., a 5PS of 3).²¹

Radiation Therapy

RT was administered as three-dimensional (3D) conformal radiation, proton beam radiotherapy, or intensity-modulated radiation therapy (IMRT). IMRT was generally used after 2010 and involved a “butterfly” technique.²⁷ Radiation was initiated at 3–6 weeks after completion of systemic therapy to an intended dose of 30–39.6 Gy for patients with a presumed complete response. In general, our institutional standard for consolidative RT was to administer 39.6 Gy. Patients with known residual active disease after treatment with curative intent received RT doses of 40–45 Gy.

Statistical Analysis

OS was calculated from the date of initial chemotherapy to the date of last follow-up or death from any cause. PFS was calculated from the start date of immunochemotherapy to the date of documented progression, relapse, or death. Patients free of disease progression and relapse were censored on the date of last follow-up visit or contact. Survival analyses were done with the Kaplan-Meier method, with statistical differences evaluated with the log-rank test.²⁸ The maximum standard uptake value (SUV_max) based on body weight is routinely recorded at our institution and was obtained from clinical reports. The Mann Whitney U (Wilcoxon rank sum) test was used to evaluate differences in median SUV_max, with a P value of ≤0.05 considered significant. Because of the low number of events in the group, univariate and multivariate analyses to identify factors associated with disease progression or recurrence were not done.

Results

Treatment

Characteristics of the 97 patients analyzed are listed in Table 1. Their median age was 35 years, and a slight majority (n=54, 56%) were women. All patients received 4–8 cycles of immunochemotherapy. Most patients (n=50) had received R-CHOP, with a median number of 6 cycles (Table 2). R-HCVAD was given to 22 patients, and R-EPOCH to 25 patients. RT was given to 72 patients (74%). Of patients treated with R-CHOP, most received RT, as this is standard practice at our institution when R-CHOP is given; RT was omitted in 5 patients given R-CHOP (10%) because of refusal (2 patients), prior surgical resection at diagnosis (2 patients), and provider preference (1 patient). Among the 22 patients treated with R-HCVAD, 4 patients (18%) did not receive RT, either because of refusal (1 patient) or provider preference (3 patients). Hence, most patients treated with either R-CHOP or R-HCVAD received radiation, in contrast to the R-EPOCH group, for which RT was not given to 16 patients (64%; Table 2). Our institutional policy is that RT can be omitted for patients with PMBL treated with R-EPOCH. Of the 9 patients who did receive radiation after R-EPOCH, 4 were treated for progressive disease and 5 received consolidative RT because of physician preference. Eight patients received an autologous stem cell transplant after immunochemotherapy (7 for progressive disease and 1 for consolidation) and 1 received an allogeneic stem cell transplant for disease relapse 1 year after an autologous transplant; this patient was still alive at last follow-up.

Table 1.

Patient and Treatment Characteristics

All Patients	Characteristic
Age, years
Median (range)	35 (19–70)
No. ≥ 50	10 (10.3%)
Sex
Male	43 (44%)
Female	54 (56%)
“B” symptoms
Yes	25 (26%)
No	72 (74%)
Disease stage
I	32 (33%)
II	56 (67%)
Bulky disease
>10-cm axial diameter	50 (51%)
>7.5-cm axial diameter	73 (75%)
Mean axial diameter, cm	10.2
Extramediastinal contiguous disease
Yes	12 (12.4%)
No
IPI
0	40 (41%)
1	56 (58%)
2	1 (1%)
Serum LDH, IU/L
>ULN*	54 (56%)
Median (Range)	756 (256–3021)

^*Normal range is defined as 213–618 IU/L

Abbreviations: R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; R-HCVAD, rituximab, fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone; R-EPOCH, rituximab, vincristine, and prednisone with dose-adjusted etoposide, doxorubicin and cyclophosphamide; IPI, International Prognostic Index; LDH, lactate dehydrogenase; ULN, upper limit of normal.

Table 2.

Treatment Characteristics

Characteristic	R-CHOP (n=50)	R-HCVAD (n=22)	R-EPOCH (n=25)
Number of cycles
Median	6	6	6
Range	5–8	5–8	4–7
Radiation Therapy
Consolidative (presumed CR)	42 (84%)	17 (77.2%)	5 (20%)
Salvage	3 (6%)	1 (4.5%)	4 (16%)
No Radiation	5 (10%)	4 (18.2%)	16 (64%)
Radiation Dose
Median (Gy)	39.6	39.6	39.6
Range (Gy)	30–45	16.2–45	30.6–43.2
Radiation Technique
3D	36 (80%)	16 (88.9%)	1 (11.1%)
IMRT	6 (13.3%)	1 (5.6%)	7 (77.8%)
Protons	3 (6.7%)	1 (5.6%)	1 (11.1%)

Outcomes

At a median follow-up time of 57 months (range 4–155 months), the 5-year PFS and OS rates for the entire group were 91% and 99% (Figure 1). Nine patients experienced disease progression (n=8) or disease relapse (n=1) at a median 4.6 months (range 2.8–8.7 months) after treatment. One patient died of disease, but no deaths related to treatment or toxicity were reported. The median OS and PFS times have not been reached. No statistically significant differences were found in 5-year PFS among patients in the 3 immunochemotherapy-regimen groups (Figure 2).

Figure 1.

Overall survival (a) and progression-free survival (b) among 97 patients treated for stage I/II primary mediastinal B cell lymphoma.

Figure 2. Progression-free survival according to type of immunochemotherapy for 97 patients with limited-stage primary mediastinal B-cell lymphoma.

Abbreviations: R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R-HCVAD, rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone; R-EPOCH, rituximab plus dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisone.

Toxicity

Treatment was well tolerated. Of the 72 patients who received radiation, 40 (56%) experienced reversible grade 1 or 2 esophagitis or dermatitis related to the treatment. Five patients experienced subacute pneumonitis requiring steroids without significant chronic pulmonary deficits. One patient experienced pericarditis after the third fraction of RT, resulting in a treatment break; however, therapy was ultimately resumed and at last follow-up this patient had a normal ejection fraction and no chronic sequelae from the pericarditis. Two secondary malignancies were reported, a gallbladder spindle cell tumor in a patient who received R-CHOP followed by consolidative RT to the mediastinum; and therapy-related myelodysplastic syndrome in another patient after 6 cycles of R-HCVAD and consolidative radiation to 30.6 Gy.

Long-term cardiac issues were observed in 5 patients. Two patients had asymptomatic declines in ejection fraction after R-CHOP that was detected on a pre-RT cardiology workup. Another patient treated with R-CHOP and RT had an asymptomatic drop in ejection fraction (from 65% to 54%) detected after being referred to cardiology for hypertension. A fourth patient had a non-fatal cardiac arrest after R-CHOP without radiation. The fifth patient experienced benign premature atrial contractions after 5 cycles of R-HCVAD and 45 Gy of RT.

PET-CT

At the time of diagnosis, 80 patients (82.5%) underwent PET-CT imaging, 11 (11.3%) had a gallium scan and 6 (6.1%) patients did not undergo functional imaging. Sixty-eight of the 97 patients (70%) had evaluable PET-CT scans after completion of all systemic therapy. Reasons for not having a PET-CT scan at that time were having had a gallium scan (n=8), an interim PET-CT scan instead of an end-of-immunochemotherapy scan (n=9) and a scan not done or unavailable (n=12). Forty-two patients (62%) had a 5PS of ≥3 and thus were considered by conventional assessment criteria to have a positive scan. Using this definition of positivity, the specificity and positive predictive value (PPV) of the end-of-treatment PET-CT were 42.6% and 16.7% (Table 3). Alternatively, if a 5PS of 4 or 5 were to be considered positive, the specificity increased to 80.3% and the PPV improved to 36.8%.

Table 3.

End of Immunochemotherapy PET-CT 5PS and Progression/Relapse Events

5PS Score	1	2	3	4	5
# Patients	0	26	23	15	4
Progression/Relapse	0	0	0	3	4

	Progression/Relapse	No Progression/Relapse
Positive 5PS 3-5	7	35
Negative 5PS 1-2	0	26

	Progression/Relapse	No Progression/Relapse
Positive 5PS 4-5	7	12
Negative 5PS 1-3	0	49

Sensitivity=100%

Specificity=42.6%

PPV=16.7%

NPV=100%

Sensitivity=100%

Specificity=80.3%

PPV=36.8%

NPV=100%

Of the 9 patients who had relapsed or progressive disease, 7 underwent PET-CT scans at the end of systemic therapy, and 3 had biopsy to confirm the relapse or progression. Of the four patients that did not undergo biopsy, the end of treatment PET-CT scan demonstrated a new avid lesion, an increase in size of the initial mediastinal mass and/or increase in SUV avidity when compared to the interim PET-CT scan. For the 2 patients who developed progressive disease but did not have a post-chemotherapy PET-CT scan, one had a grossly positive gallium scan and died of disease after salvage chemotherapy, an allogeneic stem cell transplant, and palliative radiation to the mediastinum; the other had interim PET-CT only and then experienced a biopsy proven relapse in the mediastinal radiation field 1 month after consolidative RT. For the 7 patients with progressive disease and post-immunochemotherapy PET-CT scans, all had a 5PS of 4-5 and the median SUV_max was 6.4 (Figure 3). When we compared the median SUV_max among patients with an end-of-chemotherapy 5PS of 4-5 who did or did not develop progressive disease or relapse, the difference was statistically significant (median 6.4 vs. 3.75, P<0.0027). All patients with a 5PS of 4-5 who did not have progressive disease had an SUV_max ≤5.4. Details of treatment based on immunochemotherapy and end of systemic treatment 5PS are depicted in Figure 4. When we compared the PFS of patients with 5PS scores of 1-2 versus 3-5, the difference was statistically significant (5-year PFS rates 100% vs. 82%, P<0.031, Figure 5); however, the curves diverged further when patients with a 5PS of 1-3 were compared with those with a 5PS of 4-5 (5-year PFS, 100% vs. 62%, P<0.000004).

Figure 3.

Median standardized uptake values (SUVs) on PET-CT among patients with end-of-immunochemotherapy 5PS of 4-5 with or without relapse.

Figure 4. Treatment and outcome based on type of chemoimmunotherapy and end-of-treatment PET-CT.

(a, R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R-EPOCH, rituximab plus dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisone.; b, R-HCVAD, R-HCVAD, rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone; c, R-EPOCH, rituximab plus dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisone). PET-CT, positron emission tomography-computed tomography; RT, radiation therapy; sChemo, salvage chemotherapy; CR, complete response; PD, progressive disease; ASCT, allogeneic/autologous stem cell transplant; CCR, continued complete response.

Figure 5. Progression-free survival according to 5-point [Deauville] scale (5PS) at the end of initial chemotherapy.

(a) 5PS 1-2 vs. 5PS 3-5; (b) 5PS 1-3 vs. 5PS 4-5.

Discussion

In this retrospective analysis, we show that patients with stage I/II PMBL who received RT after a complete response to rituximab and doxorubicin-containing regimens had excellent outcomes with limited acute toxicity. Roughly three-quarters of patients in our study had received RT. Approximately 10% of patients experienced disease relapse or progression after immunochemotherapy alone; however, multimodality salvage therapy with RT, additional chemotherapy, and autologous stem cell transplant was effective, resulting in highly favorable 5-year OS rates for this group of 99%.

Despite these excellent outcomes, the role of RT after immunochemotherapy for PMBL remains unclear. Retrospective studies of patients treated with R-CHOP and other anthracycline-containing regimens such as R-MACOP-B (rituximab, methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) suggest that consolidative RT improves outcomes after complete responses as well as after partial responses to systemic therapy.^14,29 This approach, however, was challenged recently by a group from Memorial Sloan Kettering Cancer Center, who published in abstract form outcomes of patients treated with R-CHOP-14 and 3 cycles of ifosfamide, carboplatin and etoposide (R-CHOP-ICE) without RT. The 3-year PFS and OS rates were 78% and 88%.³⁰ Perhaps of greater interest, though, are the outcomes of a small series of patients treated with R-EPOCH without RT in a phase II study at the NCI; the 5-year EFS rate in that study was 93%, and the OS rate was 97%. Three of 51 patients in the trial developed persistent or progressive disease, which was salvaged by RT in two patients. The 3-year PFS rate among 25 patients treated with R-EPOCH in our series, 83%, was not as favorable as in the NCI trial. Four patients in our study experienced disease progression and received salvage therapy, which included RT as a component of treatment in all four cases. Although a prospective randomized trial addressing the question of whether RT is necessary after immunochemotherapy for PMBL is ongoing (IELSG-37, NCT01599559), many centers including our own have adopted the strategy of treating PMBL with R-EPOCH and assessing response with serial PET scans without the routinely use of RT.

Considerable interest has arisen in the potential utility of functional imaging with PET-CT to guide decisions to be made at the end of systemic therapy. In the phase II NCI study, 36 patients had residual mediastinal masses and were followed with serial PET-CT scans; in 18 patients, uptake of the masses was greater than that of the MBP after chemotherapy, and residual lymphoma was found in 3 patients. PET-CT in that study had a PPV of 17% and negative predictive value of 100%. The recent prospective IELSG-26 study evaluated PET-CT after immunochemotherapy (R-CHOP, R-MACOP-B, or R-VACOP-B) in 115 patients treated for PMBL.²² Ninety-two percent of patients in that study received RT. When the cutoff for positivity was a 5PS ≥3, the PPV was similarly low at 18%. However, changing the positive cutoff to a 5PS score of 4 improved the PPV of PET-CT after immunochemotherapy to 32%. In a retrospective study from Italy, 37 patients treated with immunochemotherapy and RT had PET evaluation after systemic treatment.¹⁸ Nine of 10 patients with disease relapse or progression had a 5PS of 4 or 5. The authors of that study concluded that a score of 4 or 5 should be considered the positivity threshold for patients with PMBL and that adopting this threshold would improve the predictive power of PET-CT for this disease. In the current study, for patients with localized disease, we found strikingly similar sensitivities and specificities for PET-CT. Of the 9 patients with relapse or progression, 7 had end-of-systemic therapy PET-CT, and all had a 5PS of 4-5. Raising the cutoff for positivity from 5PS of 3 to 4 improved the PPV of PET from 16.7% to 36.8%. This change also improved specificity from 42.6% to 80.3%. Further, among all patients with a 5PS of 4-5, those with disease progression or persistent disease had higher SUV_max values (median 6.4 versus 3.75). All patients with an end-of-immunochemotherapy PET-CT 5PS of 4-5 who did not experience relapse or progression had an SUV_max of 5.4 or lower. PFS was significantly inferior for patients with 5PS of 4-5 in our series. When a 5PS of ≥3 or higher was considered positive, 62% of patients in our study had positive end-of-chemotherapy PET-CT scans. In the NCI, IELSG, and Italian studies, similar rates of FDG positivity (defined as uptake greater than that of the MBP) were found after immunochemotherapy (50%, 53%, and 68%, respectively). Thus, by increasing the threshold for the definition of positive PET scans in patients with PMBL, we may be able to enhance the predictive accuracy of PET, which may in turn help to guide decisions regarding RT, especially when RT is not a routine part of therapy.

Despite blinded PET-CT evaluation by two expert radiologists, the current study is limited by its retrospective nature. Furthermore, there were few biopsies performed among our patient cohort to exclude the possibility of a false positive result^31,32. Finally there was heterogeneity regarding the administration of consolidative RT and therefore it is challenging to assess the true sensitivity, specificity and predictive value of PET-CT imaging. Many of these limitations may be overcome when results from the IELSG-37 randomized trial become available.

In this study, three-quarters of patients were treated with RT, and treatment was well tolerated. As expected, early toxicity was grade 1 or 2 and reversible. When this paper was written, the follow-up time was too short to assess the incidence of late cardiac morbidity and second malignancies, which are of greatest concern in this young patient population. Nevertheless, it is important to recognize the ongoing evolution of RT techniques aimed at reducing normal tissue exposure, and therefore we anticipate significant decreases in late toxicity as RT techniques continue to improve. Through the use of involved-site radiation, IMRT designed to avoid cardiac structures, and customized incline boards to reduce breast exposure, the RT approaches of today are undoubtedly far superior to traditional approaches.²⁷ With a thoughtful and careful approach, RT should be considered for patients at high risk of progressive disease and relapse. Our findings indicate that patients with a 5PS of 4-5 and an SUV_max greater than 5.4 after immunochemotherapy, even R-EPOCH, should be considered at high risk for relapse and thus are candidates for therapy beyond serial imaging and observation.

Summary.

Primary Mediastinal B cell Lymphoma (PMBL) has historically been treated with immunochemotherapy and consolidative radiation with excellent treatment outcomes. The potential for late effects secondary to radiation has led to the development of more aggressive chemotherapy regimens given without routine use of radiation therapy. We found that positron emission tomography-computed tomography (PET-CT) imaging can help identify patients at high risk of progression who should be considered for additional therapy beyond chemotherapy.