- Email: [email protected]
Early Stage Extranodal Follicular Lymphoma: Characteristics, Management, and Outcomes
Original Study
Early Stage Extranodal Follicular Lymphoma: Characteristics, Management, and Outcomes Therese Andraos, Zeina Ayoub, Loretta Nastoupil, Chelsea Pinnix, Sarah Milgrom, Jillian Gunther, Sweet Ping Ng, Nathan Fowler, Sattva Neelapu, Felipe Samaniego, Bouthaina Dabaja Abstract This was a retrospective study to investigate management and outcomes of early stage extranodal follicular lymphoma patients because there is limited literature on this subgroup of patients. Although this is an indolent disease, we found a significant improvement in recurrence-free survival rates with treatment compared with observation alone. Patients who received radiation therapy as part of upfront treatment had excellent local control. The results of this study show that treatment should be individualized, and radiation can be a great option in patients for whom local control is essential. Introduction: Extranodal follicular lymphoma (E-FL) is a rare entity that has distinct characteristics and outcomes compared with nodal follicular lymphoma. Patients and Methods: This cohort comprised 37 patients with stages I/II EFL, diagnosed from 2003 to 2013. Outcomes included progression-free survival (PFS), and overall survival (OS). Survival outcomes were calculated using KaplaneMeier methods. Results: Median age was 60 years (range, 37-84 years). Disease was stage I in 29 (78.4%). The Follicular Lymphoma International Prognostic Index score was 0 to 1 in 31 (83.8%), 2 in 2 (5.4%), 3 in 1 (2.7%), and missing in 3 (8.1%). Sites of involvement included the gastrointestinal (GI) tract in 22 (59.5%), and non-GI sites in 15 (40.5%). Initial management consisted of chemotherapy (CHT) alone in 21 (56.8%), radiation therapy (RT) alone in 2 patients (5.4%), RT and rituximab in 1 (2.7%), CHT and RT in 7 (18.9%), and observation in 6 (16.2%). RT was to a median dose of 30.6 Gy (range, 23.4-44.0 Gy). At a median follow-up of 69 months (range, 8-157 months), 5-year PFS and OS were 70.4% and 94.4%, respectively. Although the 5-year PFS of those observed was worse than for those who received therapy (33.3% vs. 77.6%; P ¼ .011), that did not translate into an OS difference. Patients who received RT as part of upfront management had a 100% local control (LC) rate and a trend toward improved 5-year PFS (90% vs. 62.2%; P ¼ .067). Conclusion: Early stage E-FL is an indolent disease and is associated with excellent OS. Treatment strategies should be individualized with RT prioritized when LC is a significant goal. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2019 Elsevier Inc. All rights reserved. Keywords: Extra nodal, Follicular, Local control, Radiation therapy, Treatment
Introduction Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (NHL), comprising approximately 30% of NHL cases.1 Primarily a nodal disease, it can also
T.A. and Z.A. are first co-authors: these authors contributed equally to the work. Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Submitted: Oct 21, 2018; Revised: Jan 20, 2019; Accepted: Feb 15, 2019 Address for correspondence: Bouthaina Dabaja, MD, Department of Radiation Oncology, Unit 97, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clml.2019.02.011
arise in extranodal sites, most commonly the gastrointestinal (GI) tract, salivary glands, and orbits, among other sites.2-6 The lack of prospective studies and the rarity of this presentation lead to a variety of published data on the characteristics and outcome of extranodal FL (E-FL), as well as comparisons with nodal FL.7,8 Radiation therapy (RT) is a recommended treatment strategy, because of the excellent local response rates that are observed after modest doses of radiation. Lowry et al9 and FORT10 showed the exquisite radiosensitivity of FL. However, these trials did not focus on E-FL. Therefore, further studies that concentrate on this subgroup of patients are needed. We undertook this study, to investigate the different characteristics of stage I/II E-FL. We also compared outcomes of different treatment strategies, especially of those of GI FL patients with other E-FL patients.
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Management, and Outcomes of E-FL Table 1 Baseline Patient, Tumor, and Treatment Characteristics Characteristic
Entire Cohort (n [ 37)
GI E-FL Patients (n [ 22)
Non-GI E-FL Patients (n [ 15)
P
Median Age (Range), Years
60 (37-84)
56 (39-73)
64 (37-84)
.809
Female Sex
18 (48.6)
11 (50.0)
7 (46.7)
.842
29 (78.4)
19 (86.4)
10 (66.7)
8 (21.6)
3 (13.6)
5 (33.3)
4 (10.8)
2 (9.1)
2 (13.3)
Stage
.228
I II contiguous B Symptoms Grade
.228
1-2 3
29 (78.4)
19 (86.4)
10 (66.7)
8 (21.6)
3 (13.6)
5 (33.3)
31 (83.8)
18 (81.9)
13 (86.7)
2 (5.4)
1 (4.5)
1 (6.7)
0
1 (6.7)
FLIPI Score
.361
0-1 2 3
1 (2.7)
Missing
3 (8.1)
3 (13.6)
21 (56.8)
16 (72.7)
0
Initial Management
.060
Chemotherapy alone
5 (33.3)
RT alone
2 (5.4)
0 (0)
2 (13.3)
RT and rituximab
1 (2.7)
1 (4.5)
0 (0)
Chemotherapy and RT
7 (18.9)
2 (9.1)
5 (33.3)
Observation
6 (16.2)
3 (13.6)
3 (20.0)
6 (1-9)
8 (1-9)
6 (3-6)
Median Number Of Chemotherapy Cycles (Range) <6
6 (21.4)
4 (18.2)
2 (13.3)
6-8
19 (67.9)
11 (50.0)
6 (53.3)
>8
1 (3.6)
1 (4.5)
0 (0)
Missing
2 (7.1)
6 (27.3)
5 (33.3)
Median RT Dose (Range), Gy
.581
30.60 (23.40-44.00)
24.00 (23.40-30.60)
36.00 (30.60-44.00)
.370
.199
Data are presented as n (%) except where otherwise noted. Abbreviations: E-FL ¼ extranodal follicular lymphoma; FLIPI ¼ Follicular Lymphoma International Prognostic Index; GI ¼ gastrointestinal; RT ¼ radiation therapy.
Patients and Methods
Statistical Analysis
Patient Selection
Data analysis was performed using SPSS statistical software (IBM Corp, Armonk, NY). Overall survival (OS) was calculated from the date of diagnosis until the date of last follow-up, including death. Progression-free survival (PFS) was defined as the time from diagnosis date to disease relapse/progression or death from any cause. KaplaneMeier curves were used to compare survival outcomes, and c2 analysis was used to compare treatment plans and outcomes between GI FL and other E-FL. P values .05 were considered significant.
After receiving approval from the institutional review board, we identified and retrospectively investigated 37 patients with stage I/II E-FL seen between 2003 and 2013. In all cases, pathology was reviewed by an experienced hematopathologist at our institution and showed FL in core needle or excisional biopsy. Patients with no pathology review at M.D. Anderson Cancer Center or with no follow-up information were excluded from the study. Data on patient demographic and tumor characteristics, treatment responses, and follow-ups were collected from electronic medical records. Baseline characteristics included age, sex, date of diagnosis, stage, site of extranodal involvement, and tumor grade. Data were entered in RedCap.11 Extranodal FL patients were staged on the basis of the modified Ann Arbor Staging system. Staging was initially on the basis of imaging using positron emission tomography-computed tomography for all extranodal sites and biopsy results, including endoscopic findings in GI FL patients.
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Results Patient and Treatment Characteristics Baseline patient and tumor characteristics, as well as treatment details are summarized in Table 1. The median age was 60.0 years (range, 37-84), 19 patients were male and 29 (78.4%) had stage I disease. The Follicular Lymphoma International Prognostic Index score was 0 to 1 in 31 (83.8%), 2 in 2 (5.4%), 3 in 1 (2.7%), and missing in 3 (8.1%).
Therese Andraos et al Table 2 Characteristics, Treatment, and Sites of Failure in 11 Cases Case 1 2 3 4 5 6 7 8 9 10 11
Initial Site of Involvement
Treatment
Relapse Time, Months
Salvage Therapy
Type of Salvage Therapy
OS, Years
Buccal mucosa Left orbit Right breast Right submandibular gland Vertebra Distal small bowel Duodenum Duodenum Jejunum Liver Pancreas
Observation R-CHOP 6 cycles Observation R-CHOP 6 cycles RT (36 Gy) CHOP 9 cycles Observation Rituximab 4 cycles Resection then observation R-CHOP 6 cycles R-CHOP 6 cycles
14 47 3 85 73 12 9 36 9 Missing 69
Yes Yes Yes No Yes Yes Yes No Yes Missing Yes
Rituximab RT Rituximab 4 cycles Observation R-CHOP 4 cycles RFND 6 cycles Rituximab and lenalidomide Observation Rituximab Missing Missing
8.75 9.92 1.92 7.08 6.08 9.17 3.33 3.00 3.50 3.08 13.08
Abbreviations: OS ¼ overall survival; R-CHOP ¼ rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; RFND ¼ rituximab, fludarabine, mitoxantrone, dexamethasone; RT ¼ radiation therapy.
Disease involved the GI tract in 22 patients (59.5%). Of these, 18 patients had small intestine involvement (9 had duodenal involvement), 1 liver, 2 pancreatic, and 1 colon. Non-GI involvement was found in 15 patients (40.5%). The non-GI cohort included 3 patients with vertebral body involvement, 3 salivary gland, 2 breast, and 1 of each of the following locations: nasopharynx, thyroid gland, base of tongue, bronchial wall, buccal mucosa, orbit, and paraspinal FL. Initial management consisted of chemotherapy alone in 21 (56.8%), RT alone in 2 patients (5.4%), RT and rituximab in 1 (2.7%), chemotherapy and RT in 7 (18.9%), and observation in 6 (16.2%). The median radiation dose was 30.6 Gy (range, 23.4-44.0 Gy), which was given using involved site RT guidelines.12 The systemic therapy regimens used included: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; n ¼ 16; 57.1%), rituximab alone (n ¼ 5; 17.9%), R-CVP (rituximab, cyclophosphamide, vincristine, and prednisolone; n ¼ 3; 10.7%), ibritumomab (n ¼ 2; 7.1%), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; n ¼ 1; 3.6%), and PCR (pentostatin, cyclophosphamide, rituximab; n ¼ 1; 3.6%). The treatment strategy differed according to site; it was generally given at the discretion of the treating physician. The initial management of GI cases (n ¼ 22) was mainly with systemic therapy, including chemotherapy (n ¼ 16), chemotherapy and RT (n ¼ 2), rituximab and RT (n ¼ 1), and observation (n ¼ 3). It is noteworthy to mention that 5 GI patients with small intestine involvement underwent surgical resection of their disease before receiving adjuvant therapy. However, the treatment of non-GI cases (n ¼ 15) consisted of chemotherapy (n ¼ 5), chemotherapy and RT (n ¼ 5), RT (n ¼ 2), and observation (n ¼ 3). In the whole cohort 6 patients were observed (3 GI, 3 non-GI). The GI cases included 2 with duodenal and 1 with jejunal involvement. The non-GI cases included 1 with buccal mucosa and 2 with breast involvement. Four eventually received treatment and 2 had not received any treatment at the time of last follow-up. One of the patients with GI involvement underwent observation post
resection of disease and had local relapse 9 months later, which required treatment with rituximab. Time to treatment in the observed subgroup of patients ranged from 3 months to 14 months with a median of 9 months from diagnosis.
Site of Failures Transformation to high-grade disease was not observed in this patient population. Relapses were observed in 6 of 22 patients in the GI group, of whom 4 (66.6%) had local relapses at the initial site of extranodal involvement. In the non-GI group, disease relapse occurred in 5 of 15 patients of whom 3 (60%) were local relapses. Table 2 shows the patient characteristics, treatment, and relapse sites of these 11 cases. Distant relapses occurred in 3 patients who initially had submandibular (1 case), vertebral (1 case), and duodenal disease (1 case). The patient with submandibular disease received 6 cycles of R-CHOP and had disease recurrence in retroperitoneal lymph nodes (LNs). The second patient with vertebral FL received RT alone and had disease recurrence in mesenteric LNs. The third patient had duodenal disease, received 4 cycles of rituximab, and had disease relapse in mesenteric LNs.
Table 3 Univariate Analysis of Factors Affecting PFS Rates in the Whole Cohort Variable Age B Symptoms Sex Grade Stage GI versus non-GI Observation RT RT dose
HR (95% CI) 1.051 1.860 0.401 0.395 1.863 0.550 4.333 0.199 1.001
(0.993-1.112) (0.371-9.334) (0.106-1.515) (0.050-3.089) (0.489-7.099) (0.168-1.804) (1.252-14.997) (0.025-1.563) (0.998-1.004)
P .087 .451 .178 .376 .362 .324 .021 .125 .519
Abbreviations: GI ¼ gastrointestinal; RT ¼ radiation therapy.
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Management, and Outcomes of E-FL Table 4 Univariate Analysis of Factors Affecting PFS Rates in the GI Cohort versus Non-GI Cohort GI Cohort Variable Age B symptoms Sex Grade Stage Observation RT
HR (95% CI) 1.052 2.333 0.292 0.042 2.044 6.014 0.036
(0.958-1.156) (0.198-27.443) (0.032-2.635) (0.000-51388.81) (0.228-18.349) (0.960-37.689) (0.000-778.928)
Non-GI Cohort P .288 .501 .273 .657 .523 .055 .514
HR (95% CI) 1.038 1.570 0.524 0.366 1.241 2.960 0.164
(0.961-1.122) (0.174-14.141) (0.095-2.886) (0.042-3.150) (0.221-6.968) (0.536-16.344) (0.019-1.415)
P .340 .688 .458 .360 .806 .213 .100
Abbreviations: GI ¼ gastrointestinal; HR ¼ hazard ratio; RT ¼ radiation therapy.
Figure 1 KaplaneMaier Curve Showing (A) Progression-Free Survival and (B) Overall Survival Rates in Gastrointestinal (GI) versus Non-GI Cases
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Therese Andraos et al Univariate Analysis
Survival
No disease or patient characteristic was significantly associated with PFS in this cohort (Table 3). Age, sex, B symptoms, grade, stage, and initial site of extranodal disease had no effect on PFS in our cohort. Regarding treatment-related factors, patients who were observed had a significantly higher relapse rate compared with those who received initial therapy (P ¼ .021). The risk of disease relapse did not differ according to treatment strategy in univariate analysis, excluding patients who were observed; however, patients who were observed had a significantly higher progression rate (4/6; 66.6%) compared with those who received any treatment. After stratifying patients on the basis of the location of their extranodal disease, observation was still negatively associated with a higher risk for relapse especially for those with PFS in the GI cohort (P ¼ .055; Table 4).
At a median follow-up of 69 months (range, 8-157 months), 5-year PFS and OS were 70.4% and 94.4%, respectively. These rates were 80.4% and 100% for GI cases, and 57.8% and 86.2% for non-GI cases (P ¼ .314; P ¼ .163; Figure 1). Patients who were observed experienced worse PFS than those who received upfront therapy (5-year PFS 33.3% vs. 77.6%; P ¼ .011), with no difference in OS (P ¼ .623; Figure 2). In patients who received RT as a part of upfront management, no local relapse was observed, and there was a trend toward improved local control (LC; 5year LC 100% vs. 74.0%; P ¼ .058), with no significant effect on PFS (Figure 3). Among patients who received RT, there was no difference in PFS rates when stratified according to GI or non-GI involvement (P ¼ .513), and no local relapse was observed in either group. We also compared PFS rates among patients who received chemotherapy and RT versus patients who received chemotherapy
Figure 2 KaplaneMaier Curve Showing (A) Progression-Free Survival and (B) Overall Survival Rates in Patients Who Received Upfront Treatment Compared With Those Observed
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Management, and Outcomes of E-FL Figure 3 KaplaneMaier Curve Showing (A) Progression-Free Survival and (B) Local Recurrence-Free Survival Rates in Patients Who Received Radiation Therapy (RT) as Part of Their Initial Management
alone; there was a borderline significant added value on 5-year PFS in patients who received combination therapy (P ¼ .067; Figure 4A). When this subgroup of patients was stratified into GI and non-GI, 5-year PFS rates were significantly higher in the nonGI FL patients who received chemotherapy and RT (P ¼ .033; Figure 4B) but did not have an effect on GI FL (P ¼ .405; Figure 4C). It is worth mentioning that in patients who received RT as part of their treatment, radiation-induced toxicity was observed in 6 of 10 patients, and was limited to Grade 1 dermatitis (2/6 patients; 33.3%), Grade 1 nausea (2/6 patients, 33.3%), and mucositis (Grade 1 in 3/6 patients; Grade 2 in 1/6 patients.)
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Discussion In this cohort of patients with early-stage E-FL, survival outcomes were excellent. However, patients who underwent observation only experienced higher rates of progression than those who were treated with systemic therapy or RT. It is noteworthy to mention that this is a historic series and does not reflect our current management of these patients. Because of the data showing excellent outcomes for these patients, we currently typically use a more minimal approach, such as observation or low-dose RT. Gastrointestinal FL is a distinct entity, which has been proposed to have a favorable disease course, with observation proposed as an initial treatment strategy on the basis of several retrospective studies.
Therese Andraos et al Figure 4 KaplaneMaier Curve Showing Progression-Free Survival Rates in Patients Who Received Chemotherapy With or Without Radiation Therapy (RT) in (A) All Cohort, (B) Non-Gastrointestinal (GI) Cases, and (C) GI Cases
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Management, and Outcomes of E-FL
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Lightner et al13 investigated primary GI FL patients who had asymptomatic disease, and concluded that observation can be a valid option in patients with early stage GI FL disease. Schmatz et al14 focused on 63 duodenal stage I FL cases. Most of the patients (n ¼ 24; 38.1%) were observed only and 19 patients (30.2%) received radiation alone. Rituximab alone was given to 5 patients (7.9%), whereas 8 patients (12.7%) received chemotherapy with or without RT. Two patients had the Whipple procedure and the remaining patients had no control endoscopy so treatment outcome could not be assessed. Interestingly, in the observation group, 7 of 24 patients had spontaneous regression of their lesions, but in 17 patients disease was noted to be stable. Patients who received RT alone achieved 100% LC without significant toxicity at a median follow-up of 37 months. Similarly, we observed no influence of treatment on OS, however, in our study observation was associated with inferior PFS. RT to a moderate dose is an upfront strategy to consider because it is associated with minimal long-term toxicity as seen in the aforementioned Journal of Clinical Oncology study and for some patients it will likely result in less frequent endoscopic biopsy for disease monitoring. Another study supporting the watch and wait policy was published by Tari et al15 on 28 patients with GI FL with all cases involving the small bowel. Sixty-one percent of the patients were observed and OS rates were 100% at median follow-up of 41 months. A French study by Damaj et al16 also investigated 25 FL patients with small bowel involvement stage I to IV, of whom 28% were observed; they concluded that treatment might not be required unless there is proof of disease progression or the patient becomes symptomatic. All of these aforementioned studies show no benefit of treatment in GI FL patients on OS rates, which is similar to our findings. Our findings are in agreement with the overall management of nodal FL for which patient’s treatment strategy does not affect the OS especially in early stage disease. That made it acceptable to deliver local radiation with minimal toxicity and reserve systemic therapy for when disease relapse occurs in a distant location. Friedberg et al17 investigated 471 patients with stage I FL. They concluded that PFS was significantly improved with either rituximab and chemotherapy or systemic therapy with RT compared with patients who receive RT alone; however, there were no differences in OS rates. Although patients who presented with GI locations tended to be managed with systemic chemotherapy, that was most probably to avoid radiation, and that can be challenging in abdominal/intestinal locations. With the recent advances in radiation treatment delivery techniques coupled with daily imaging to assess the accuracy of targeting the area of interest, that might be the reason for the paradigm shift seen in our patients; in later years radiation was used instead of systemic chemotherapy, which could shift the treatment strategy toward using radiation in these cases. Additionally, the current standard of care is a very modest dose of radiation on the basis of a recent publication by Lowry et al, which established a dose of 24 Gy as the standard of care.9 An ultra-low dose of 4 Gy (FORT trial) has been also tried and suggested in certain patients. Both studies point to the fact that FL is highly sensitive to radiation and moving to an approach that could include radiation seems to be safe and has a low potential for acute and longterm toxicities.
Clinical Lymphoma, Myeloma & Leukemia Month 2019
Our results confirm the previously published data from Stanford University,7 which showed no significant difference in survival outcomes between E-FL and nodal FL. Their early stage extranodal cohort mainly consisted of 8 patients with salivary gland FL and 9 patients with GI FL, with the remaining 10 cases involving the thyroid, eye, uvula, testes, ovaries, and spleen. Seven patients were treated with radiation with or without chemotherapy. The rest of the patients with available follow-up were observed. When the GI cohort was compared with the rest of the extranodal cases, no difference in survival outcomes was observed. Chouhan et al8 used the Surveillance, Epidemiology, and End Results Registry to investigate the different clinical characteristics of GI FL patients and the survival outcomes on the basis of the initial site of involvement. They showed that patients with small intestine FL had better 5-year OS outcomes compared with gastric and colorectal cases. Our study has several limitations including its retrospective nature, small sample size, and the treatment strategies being decided at the discretion of the medical oncologist, and often avoiding radiation in GI locations. The fact that others had found similar results confirms the current guidelines that we use at our institution.
Conclusion Limited stage presentation of E-FL is relatively rare, making the ability to conduct large prospective trials difficult. This singleinstitution series suggests that first-line therapy with minimally toxic regimens is preferred, because OS was not affected by the initial treatment strategy. RT with or without CDe20-directed immunotherapy can offer excellent LC and superior PFS compared with observation. More aggressive strategies with cytotoxic chemotherapy may be reserved for patients who experience relapse or transformation.
Clinical Practice Points Follicular lymphoma is the most common subtype of indolent
NHL, which is primarily a nodal disease, but can also arise in extranodal sites, most commonly the GI tract. We undertook this study to investigate the different characteristics and treatment strategies of stage I/II E-FL because there are no clear data on the approach to treat these cases. Our results show that patients who undergo treatment have better PFS rates compared with those who are observed only. Therefore, using an approach that could control the disease with the least toxicity, which currently includes RT alone or with rituximab, could be a great option for these patients, while reserving systemic therapy for when the disease relapses or transforms.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Pugh TJ, Ballonoff A, Newman F, Rabinovitch R. Improved survival in patients with early stage low-grade follicular lymphoma treated with radiation: a Surveillance, Epidemiology, and End Results database analysis. Cancer 2010; 116:3843-51. 2. Derringer GA, Thompson LD, Frommelt RA, Bijwaard KE, Heffess CS, Abbondanzo SL. Malignant lymphoma of the thyroid gland: a clinicopathologic study of 108 cases. Am J Surg Pathol 2000; 24:623-39.
Therese Andraos et al 3. Ferry JA, Harris NL, Young RH, Coen J, Zietman A, Scully RE. Malignant lymphoma of the testis, epididymis, and spermatic cord. A clinicopathologic study of 69 cases with immunophenotypic analysis. Am J Surg Pathol 1994; 18: 376-90. 4. Ferry JA, Fung CY, Zukerberg L, et al. Lymphoma of the ocular adnexa: a study of 353 cases. Am J Surg Pathol 2007; 31:170-84. 5. Kojima M, Shimizu K, Nishikawa M, et al. Primary salivary gland lymphoma among Japanese: a clinicopathological study of 30 cases. Leuk Lymphoma 2007; 48: 1793-8. 6. Yoshino T, Miyake K, Ichimura K, et al. Increased incidence of follicular lymphoma in the duodenum. Am J Surg Pathol 2000; 24:688-93. 7. Weinberg OK, Ma L, Seo K, et al. Low stage follicular lymphoma: biologic and clinical characterization according to nodal or extranodal primary origin. Am J Surg Pathol 2009; 33:591-8. 8. Chouhan J, Batra S, Gupta R, Guha S. Gastrointestinal follicular lymphoma: using primary site as a predictor of survival. Cancer Med 2016; 5:2669-77. 9. Lowry L, Smith P, Qian W, et al. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. Radiother Oncol 2011; 100: 86-92. 10. Hoskin PJ, Kirkwood AA, Popova B, et al. 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol 2014; 15:457-63.
11. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap) - a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42:377-81. 12. Yahalom J, Illidge T, Specht L, et al. Modern radiation therapy for extranodal lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys 2014; 89:49-58. 13. Lightner AL, Shannon E, Gibbons MM, Russell MM. Primary gastrointestinal non-Hodgkin lymphoma of the small and large intestines: a systematic review. J Gastrointest Surg 2016; 20:827-39. 14. Schmatz AI, Streubel B, Kretschmer-Chott E, et al. Primary follicular lymphoma of the duodenum is a distinct mucosal/submucosal variant of follicular lymphoma: a retrospective study of 63 cases. J Clin Oncol 2011; 29:1445-51. 15. Tari A, Asaoku H, Kunihiro M, Tanaka S, Fujihara M, Yoshino T. Clinical features of gastrointestinal follicular lymphoma: comparison with nodal follicular lymphoma and gastrointestinal MALT lymphoma. Digestion 2011; 83:191-7. 16. Damaj G, Verkarre V, Delmer A, et al. Primary follicular lymphoma of the gastrointestinal tract: a study of 25 cases and a literature review. Ann Oncol 2003; 14:623-9. 17. Friedberg JW, Byrtek M, Link BK, et al. Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study. J Clin Oncol 2012; 30:3368-75.
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Early Stage Extranodal Follicular Lymphoma: Characteristics, Management, and Outcomes Therese Andraos, Zeina Ayoub, Loretta Nastoupil, Chelsea Pinnix, Sarah Milgrom, Jillian Gunther, Sweet Ping Ng, Nathan Fowler, Sattva Neelapu, Felipe Samaniego, Bouthaina Dabaja Abstract This was a retrospective study to investigate management and outcomes of early stage extranodal follicular lymphoma patients because there is limited literature on this subgroup of patients. Although this is an indolent disease, we found a significant improvement in recurrence-free survival rates with treatment compared with observation alone. Patients who received radiation therapy as part of upfront treatment had excellent local control. The results of this study show that treatment should be individualized, and radiation can be a great option in patients for whom local control is essential. Introduction: Extranodal follicular lymphoma (E-FL) is a rare entity that has distinct characteristics and outcomes compared with nodal follicular lymphoma. Patients and Methods: This cohort comprised 37 patients with stages I/II EFL, diagnosed from 2003 to 2013. Outcomes included progression-free survival (PFS), and overall survival (OS). Survival outcomes were calculated using KaplaneMeier methods. Results: Median age was 60 years (range, 37-84 years). Disease was stage I in 29 (78.4%). The Follicular Lymphoma International Prognostic Index score was 0 to 1 in 31 (83.8%), 2 in 2 (5.4%), 3 in 1 (2.7%), and missing in 3 (8.1%). Sites of involvement included the gastrointestinal (GI) tract in 22 (59.5%), and non-GI sites in 15 (40.5%). Initial management consisted of chemotherapy (CHT) alone in 21 (56.8%), radiation therapy (RT) alone in 2 patients (5.4%), RT and rituximab in 1 (2.7%), CHT and RT in 7 (18.9%), and observation in 6 (16.2%). RT was to a median dose of 30.6 Gy (range, 23.4-44.0 Gy). At a median follow-up of 69 months (range, 8-157 months), 5-year PFS and OS were 70.4% and 94.4%, respectively. Although the 5-year PFS of those observed was worse than for those who received therapy (33.3% vs. 77.6%; P ¼ .011), that did not translate into an OS difference. Patients who received RT as part of upfront management had a 100% local control (LC) rate and a trend toward improved 5-year PFS (90% vs. 62.2%; P ¼ .067). Conclusion: Early stage E-FL is an indolent disease and is associated with excellent OS. Treatment strategies should be individualized with RT prioritized when LC is a significant goal. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2019 Elsevier Inc. All rights reserved. Keywords: Extra nodal, Follicular, Local control, Radiation therapy, Treatment
Introduction Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (NHL), comprising approximately 30% of NHL cases.1 Primarily a nodal disease, it can also
T.A. and Z.A. are first co-authors: these authors contributed equally to the work. Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Submitted: Oct 21, 2018; Revised: Jan 20, 2019; Accepted: Feb 15, 2019 Address for correspondence: Bouthaina Dabaja, MD, Department of Radiation Oncology, Unit 97, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clml.2019.02.011
arise in extranodal sites, most commonly the gastrointestinal (GI) tract, salivary glands, and orbits, among other sites.2-6 The lack of prospective studies and the rarity of this presentation lead to a variety of published data on the characteristics and outcome of extranodal FL (E-FL), as well as comparisons with nodal FL.7,8 Radiation therapy (RT) is a recommended treatment strategy, because of the excellent local response rates that are observed after modest doses of radiation. Lowry et al9 and FORT10 showed the exquisite radiosensitivity of FL. However, these trials did not focus on E-FL. Therefore, further studies that concentrate on this subgroup of patients are needed. We undertook this study, to investigate the different characteristics of stage I/II E-FL. We also compared outcomes of different treatment strategies, especially of those of GI FL patients with other E-FL patients.
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Management, and Outcomes of E-FL Table 1 Baseline Patient, Tumor, and Treatment Characteristics Characteristic
Entire Cohort (n [ 37)
GI E-FL Patients (n [ 22)
Non-GI E-FL Patients (n [ 15)
P
Median Age (Range), Years
60 (37-84)
56 (39-73)
64 (37-84)
.809
Female Sex
18 (48.6)
11 (50.0)
7 (46.7)
.842
29 (78.4)
19 (86.4)
10 (66.7)
8 (21.6)
3 (13.6)
5 (33.3)
4 (10.8)
2 (9.1)
2 (13.3)
Stage
.228
I II contiguous B Symptoms Grade
.228
1-2 3
29 (78.4)
19 (86.4)
10 (66.7)
8 (21.6)
3 (13.6)
5 (33.3)
31 (83.8)
18 (81.9)
13 (86.7)
2 (5.4)
1 (4.5)
1 (6.7)
0
1 (6.7)
FLIPI Score
.361
0-1 2 3
1 (2.7)
Missing
3 (8.1)
3 (13.6)
21 (56.8)
16 (72.7)
0
Initial Management
.060
Chemotherapy alone
5 (33.3)
RT alone
2 (5.4)
0 (0)
2 (13.3)
RT and rituximab
1 (2.7)
1 (4.5)
0 (0)
Chemotherapy and RT
7 (18.9)
2 (9.1)
5 (33.3)
Observation
6 (16.2)
3 (13.6)
3 (20.0)
6 (1-9)
8 (1-9)
6 (3-6)
Median Number Of Chemotherapy Cycles (Range) <6
6 (21.4)
4 (18.2)
2 (13.3)
6-8
19 (67.9)
11 (50.0)
6 (53.3)
>8
1 (3.6)
1 (4.5)
0 (0)
Missing
2 (7.1)
6 (27.3)
5 (33.3)
Median RT Dose (Range), Gy
.581
30.60 (23.40-44.00)
24.00 (23.40-30.60)
36.00 (30.60-44.00)
.370
.199
Data are presented as n (%) except where otherwise noted. Abbreviations: E-FL ¼ extranodal follicular lymphoma; FLIPI ¼ Follicular Lymphoma International Prognostic Index; GI ¼ gastrointestinal; RT ¼ radiation therapy.
Patients and Methods
Statistical Analysis
Patient Selection
Data analysis was performed using SPSS statistical software (IBM Corp, Armonk, NY). Overall survival (OS) was calculated from the date of diagnosis until the date of last follow-up, including death. Progression-free survival (PFS) was defined as the time from diagnosis date to disease relapse/progression or death from any cause. KaplaneMeier curves were used to compare survival outcomes, and c2 analysis was used to compare treatment plans and outcomes between GI FL and other E-FL. P values .05 were considered significant.
After receiving approval from the institutional review board, we identified and retrospectively investigated 37 patients with stage I/II E-FL seen between 2003 and 2013. In all cases, pathology was reviewed by an experienced hematopathologist at our institution and showed FL in core needle or excisional biopsy. Patients with no pathology review at M.D. Anderson Cancer Center or with no follow-up information were excluded from the study. Data on patient demographic and tumor characteristics, treatment responses, and follow-ups were collected from electronic medical records. Baseline characteristics included age, sex, date of diagnosis, stage, site of extranodal involvement, and tumor grade. Data were entered in RedCap.11 Extranodal FL patients were staged on the basis of the modified Ann Arbor Staging system. Staging was initially on the basis of imaging using positron emission tomography-computed tomography for all extranodal sites and biopsy results, including endoscopic findings in GI FL patients.
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Results Patient and Treatment Characteristics Baseline patient and tumor characteristics, as well as treatment details are summarized in Table 1. The median age was 60.0 years (range, 37-84), 19 patients were male and 29 (78.4%) had stage I disease. The Follicular Lymphoma International Prognostic Index score was 0 to 1 in 31 (83.8%), 2 in 2 (5.4%), 3 in 1 (2.7%), and missing in 3 (8.1%).
Therese Andraos et al Table 2 Characteristics, Treatment, and Sites of Failure in 11 Cases Case 1 2 3 4 5 6 7 8 9 10 11
Initial Site of Involvement
Treatment
Relapse Time, Months
Salvage Therapy
Type of Salvage Therapy
OS, Years
Buccal mucosa Left orbit Right breast Right submandibular gland Vertebra Distal small bowel Duodenum Duodenum Jejunum Liver Pancreas
Observation R-CHOP 6 cycles Observation R-CHOP 6 cycles RT (36 Gy) CHOP 9 cycles Observation Rituximab 4 cycles Resection then observation R-CHOP 6 cycles R-CHOP 6 cycles
14 47 3 85 73 12 9 36 9 Missing 69
Yes Yes Yes No Yes Yes Yes No Yes Missing Yes
Rituximab RT Rituximab 4 cycles Observation R-CHOP 4 cycles RFND 6 cycles Rituximab and lenalidomide Observation Rituximab Missing Missing
8.75 9.92 1.92 7.08 6.08 9.17 3.33 3.00 3.50 3.08 13.08
Abbreviations: OS ¼ overall survival; R-CHOP ¼ rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; RFND ¼ rituximab, fludarabine, mitoxantrone, dexamethasone; RT ¼ radiation therapy.
Disease involved the GI tract in 22 patients (59.5%). Of these, 18 patients had small intestine involvement (9 had duodenal involvement), 1 liver, 2 pancreatic, and 1 colon. Non-GI involvement was found in 15 patients (40.5%). The non-GI cohort included 3 patients with vertebral body involvement, 3 salivary gland, 2 breast, and 1 of each of the following locations: nasopharynx, thyroid gland, base of tongue, bronchial wall, buccal mucosa, orbit, and paraspinal FL. Initial management consisted of chemotherapy alone in 21 (56.8%), RT alone in 2 patients (5.4%), RT and rituximab in 1 (2.7%), chemotherapy and RT in 7 (18.9%), and observation in 6 (16.2%). The median radiation dose was 30.6 Gy (range, 23.4-44.0 Gy), which was given using involved site RT guidelines.12 The systemic therapy regimens used included: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; n ¼ 16; 57.1%), rituximab alone (n ¼ 5; 17.9%), R-CVP (rituximab, cyclophosphamide, vincristine, and prednisolone; n ¼ 3; 10.7%), ibritumomab (n ¼ 2; 7.1%), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; n ¼ 1; 3.6%), and PCR (pentostatin, cyclophosphamide, rituximab; n ¼ 1; 3.6%). The treatment strategy differed according to site; it was generally given at the discretion of the treating physician. The initial management of GI cases (n ¼ 22) was mainly with systemic therapy, including chemotherapy (n ¼ 16), chemotherapy and RT (n ¼ 2), rituximab and RT (n ¼ 1), and observation (n ¼ 3). It is noteworthy to mention that 5 GI patients with small intestine involvement underwent surgical resection of their disease before receiving adjuvant therapy. However, the treatment of non-GI cases (n ¼ 15) consisted of chemotherapy (n ¼ 5), chemotherapy and RT (n ¼ 5), RT (n ¼ 2), and observation (n ¼ 3). In the whole cohort 6 patients were observed (3 GI, 3 non-GI). The GI cases included 2 with duodenal and 1 with jejunal involvement. The non-GI cases included 1 with buccal mucosa and 2 with breast involvement. Four eventually received treatment and 2 had not received any treatment at the time of last follow-up. One of the patients with GI involvement underwent observation post
resection of disease and had local relapse 9 months later, which required treatment with rituximab. Time to treatment in the observed subgroup of patients ranged from 3 months to 14 months with a median of 9 months from diagnosis.
Site of Failures Transformation to high-grade disease was not observed in this patient population. Relapses were observed in 6 of 22 patients in the GI group, of whom 4 (66.6%) had local relapses at the initial site of extranodal involvement. In the non-GI group, disease relapse occurred in 5 of 15 patients of whom 3 (60%) were local relapses. Table 2 shows the patient characteristics, treatment, and relapse sites of these 11 cases. Distant relapses occurred in 3 patients who initially had submandibular (1 case), vertebral (1 case), and duodenal disease (1 case). The patient with submandibular disease received 6 cycles of R-CHOP and had disease recurrence in retroperitoneal lymph nodes (LNs). The second patient with vertebral FL received RT alone and had disease recurrence in mesenteric LNs. The third patient had duodenal disease, received 4 cycles of rituximab, and had disease relapse in mesenteric LNs.
Table 3 Univariate Analysis of Factors Affecting PFS Rates in the Whole Cohort Variable Age B Symptoms Sex Grade Stage GI versus non-GI Observation RT RT dose
HR (95% CI) 1.051 1.860 0.401 0.395 1.863 0.550 4.333 0.199 1.001
(0.993-1.112) (0.371-9.334) (0.106-1.515) (0.050-3.089) (0.489-7.099) (0.168-1.804) (1.252-14.997) (0.025-1.563) (0.998-1.004)
P .087 .451 .178 .376 .362 .324 .021 .125 .519
Abbreviations: GI ¼ gastrointestinal; RT ¼ radiation therapy.
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Management, and Outcomes of E-FL Table 4 Univariate Analysis of Factors Affecting PFS Rates in the GI Cohort versus Non-GI Cohort GI Cohort Variable Age B symptoms Sex Grade Stage Observation RT
HR (95% CI) 1.052 2.333 0.292 0.042 2.044 6.014 0.036
(0.958-1.156) (0.198-27.443) (0.032-2.635) (0.000-51388.81) (0.228-18.349) (0.960-37.689) (0.000-778.928)
Non-GI Cohort P .288 .501 .273 .657 .523 .055 .514
HR (95% CI) 1.038 1.570 0.524 0.366 1.241 2.960 0.164
(0.961-1.122) (0.174-14.141) (0.095-2.886) (0.042-3.150) (0.221-6.968) (0.536-16.344) (0.019-1.415)
P .340 .688 .458 .360 .806 .213 .100
Abbreviations: GI ¼ gastrointestinal; HR ¼ hazard ratio; RT ¼ radiation therapy.
Figure 1 KaplaneMaier Curve Showing (A) Progression-Free Survival and (B) Overall Survival Rates in Gastrointestinal (GI) versus Non-GI Cases
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Therese Andraos et al Univariate Analysis
Survival
No disease or patient characteristic was significantly associated with PFS in this cohort (Table 3). Age, sex, B symptoms, grade, stage, and initial site of extranodal disease had no effect on PFS in our cohort. Regarding treatment-related factors, patients who were observed had a significantly higher relapse rate compared with those who received initial therapy (P ¼ .021). The risk of disease relapse did not differ according to treatment strategy in univariate analysis, excluding patients who were observed; however, patients who were observed had a significantly higher progression rate (4/6; 66.6%) compared with those who received any treatment. After stratifying patients on the basis of the location of their extranodal disease, observation was still negatively associated with a higher risk for relapse especially for those with PFS in the GI cohort (P ¼ .055; Table 4).
At a median follow-up of 69 months (range, 8-157 months), 5-year PFS and OS were 70.4% and 94.4%, respectively. These rates were 80.4% and 100% for GI cases, and 57.8% and 86.2% for non-GI cases (P ¼ .314; P ¼ .163; Figure 1). Patients who were observed experienced worse PFS than those who received upfront therapy (5-year PFS 33.3% vs. 77.6%; P ¼ .011), with no difference in OS (P ¼ .623; Figure 2). In patients who received RT as a part of upfront management, no local relapse was observed, and there was a trend toward improved local control (LC; 5year LC 100% vs. 74.0%; P ¼ .058), with no significant effect on PFS (Figure 3). Among patients who received RT, there was no difference in PFS rates when stratified according to GI or non-GI involvement (P ¼ .513), and no local relapse was observed in either group. We also compared PFS rates among patients who received chemotherapy and RT versus patients who received chemotherapy
Figure 2 KaplaneMaier Curve Showing (A) Progression-Free Survival and (B) Overall Survival Rates in Patients Who Received Upfront Treatment Compared With Those Observed
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Management, and Outcomes of E-FL Figure 3 KaplaneMaier Curve Showing (A) Progression-Free Survival and (B) Local Recurrence-Free Survival Rates in Patients Who Received Radiation Therapy (RT) as Part of Their Initial Management
alone; there was a borderline significant added value on 5-year PFS in patients who received combination therapy (P ¼ .067; Figure 4A). When this subgroup of patients was stratified into GI and non-GI, 5-year PFS rates were significantly higher in the nonGI FL patients who received chemotherapy and RT (P ¼ .033; Figure 4B) but did not have an effect on GI FL (P ¼ .405; Figure 4C). It is worth mentioning that in patients who received RT as part of their treatment, radiation-induced toxicity was observed in 6 of 10 patients, and was limited to Grade 1 dermatitis (2/6 patients; 33.3%), Grade 1 nausea (2/6 patients, 33.3%), and mucositis (Grade 1 in 3/6 patients; Grade 2 in 1/6 patients.)
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Discussion In this cohort of patients with early-stage E-FL, survival outcomes were excellent. However, patients who underwent observation only experienced higher rates of progression than those who were treated with systemic therapy or RT. It is noteworthy to mention that this is a historic series and does not reflect our current management of these patients. Because of the data showing excellent outcomes for these patients, we currently typically use a more minimal approach, such as observation or low-dose RT. Gastrointestinal FL is a distinct entity, which has been proposed to have a favorable disease course, with observation proposed as an initial treatment strategy on the basis of several retrospective studies.
Therese Andraos et al Figure 4 KaplaneMaier Curve Showing Progression-Free Survival Rates in Patients Who Received Chemotherapy With or Without Radiation Therapy (RT) in (A) All Cohort, (B) Non-Gastrointestinal (GI) Cases, and (C) GI Cases
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Management, and Outcomes of E-FL
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Lightner et al13 investigated primary GI FL patients who had asymptomatic disease, and concluded that observation can be a valid option in patients with early stage GI FL disease. Schmatz et al14 focused on 63 duodenal stage I FL cases. Most of the patients (n ¼ 24; 38.1%) were observed only and 19 patients (30.2%) received radiation alone. Rituximab alone was given to 5 patients (7.9%), whereas 8 patients (12.7%) received chemotherapy with or without RT. Two patients had the Whipple procedure and the remaining patients had no control endoscopy so treatment outcome could not be assessed. Interestingly, in the observation group, 7 of 24 patients had spontaneous regression of their lesions, but in 17 patients disease was noted to be stable. Patients who received RT alone achieved 100% LC without significant toxicity at a median follow-up of 37 months. Similarly, we observed no influence of treatment on OS, however, in our study observation was associated with inferior PFS. RT to a moderate dose is an upfront strategy to consider because it is associated with minimal long-term toxicity as seen in the aforementioned Journal of Clinical Oncology study and for some patients it will likely result in less frequent endoscopic biopsy for disease monitoring. Another study supporting the watch and wait policy was published by Tari et al15 on 28 patients with GI FL with all cases involving the small bowel. Sixty-one percent of the patients were observed and OS rates were 100% at median follow-up of 41 months. A French study by Damaj et al16 also investigated 25 FL patients with small bowel involvement stage I to IV, of whom 28% were observed; they concluded that treatment might not be required unless there is proof of disease progression or the patient becomes symptomatic. All of these aforementioned studies show no benefit of treatment in GI FL patients on OS rates, which is similar to our findings. Our findings are in agreement with the overall management of nodal FL for which patient’s treatment strategy does not affect the OS especially in early stage disease. That made it acceptable to deliver local radiation with minimal toxicity and reserve systemic therapy for when disease relapse occurs in a distant location. Friedberg et al17 investigated 471 patients with stage I FL. They concluded that PFS was significantly improved with either rituximab and chemotherapy or systemic therapy with RT compared with patients who receive RT alone; however, there were no differences in OS rates. Although patients who presented with GI locations tended to be managed with systemic chemotherapy, that was most probably to avoid radiation, and that can be challenging in abdominal/intestinal locations. With the recent advances in radiation treatment delivery techniques coupled with daily imaging to assess the accuracy of targeting the area of interest, that might be the reason for the paradigm shift seen in our patients; in later years radiation was used instead of systemic chemotherapy, which could shift the treatment strategy toward using radiation in these cases. Additionally, the current standard of care is a very modest dose of radiation on the basis of a recent publication by Lowry et al, which established a dose of 24 Gy as the standard of care.9 An ultra-low dose of 4 Gy (FORT trial) has been also tried and suggested in certain patients. Both studies point to the fact that FL is highly sensitive to radiation and moving to an approach that could include radiation seems to be safe and has a low potential for acute and longterm toxicities.
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Our results confirm the previously published data from Stanford University,7 which showed no significant difference in survival outcomes between E-FL and nodal FL. Their early stage extranodal cohort mainly consisted of 8 patients with salivary gland FL and 9 patients with GI FL, with the remaining 10 cases involving the thyroid, eye, uvula, testes, ovaries, and spleen. Seven patients were treated with radiation with or without chemotherapy. The rest of the patients with available follow-up were observed. When the GI cohort was compared with the rest of the extranodal cases, no difference in survival outcomes was observed. Chouhan et al8 used the Surveillance, Epidemiology, and End Results Registry to investigate the different clinical characteristics of GI FL patients and the survival outcomes on the basis of the initial site of involvement. They showed that patients with small intestine FL had better 5-year OS outcomes compared with gastric and colorectal cases. Our study has several limitations including its retrospective nature, small sample size, and the treatment strategies being decided at the discretion of the medical oncologist, and often avoiding radiation in GI locations. The fact that others had found similar results confirms the current guidelines that we use at our institution.
Conclusion Limited stage presentation of E-FL is relatively rare, making the ability to conduct large prospective trials difficult. This singleinstitution series suggests that first-line therapy with minimally toxic regimens is preferred, because OS was not affected by the initial treatment strategy. RT with or without CDe20-directed immunotherapy can offer excellent LC and superior PFS compared with observation. More aggressive strategies with cytotoxic chemotherapy may be reserved for patients who experience relapse or transformation.
Clinical Practice Points Follicular lymphoma is the most common subtype of indolent
NHL, which is primarily a nodal disease, but can also arise in extranodal sites, most commonly the GI tract. We undertook this study to investigate the different characteristics and treatment strategies of stage I/II E-FL because there are no clear data on the approach to treat these cases. Our results show that patients who undergo treatment have better PFS rates compared with those who are observed only. Therefore, using an approach that could control the disease with the least toxicity, which currently includes RT alone or with rituximab, could be a great option for these patients, while reserving systemic therapy for when the disease relapses or transforms.
Disclosure The authors have stated that they have no conflicts of interest.
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