Abstract
NCCN guidelines recommend radiation therapy (RT) for localized indolent non-Hodgkin lymphomas (iNHL). Many referring physicians avoid RT to the head and neck (HN) due to fears of toxicity. Very low dose radiation (4Gy) for select patients produces sustained local control and recently gained popularity. We compared early and late toxicities of standard 24–30Gy to 4Gy in patients with HN iNHL. We retrospectively analyzed 266 consecutive patients with HN iNHL receiving RT from 1994–2017. Patient characteristics, outcomes, and toxicities were collected from medical records. Early (≤2months post-RT) and late (>2months post-RT) toxicities were graded per CTCAEv4. Grades 1–2 were defined as “low-grade” and 3–4 “high-grade”. Toxicity incidence was compared between 4Gy and >4Gy, grouped by treated site (orbit, non-orbital head, neck, skin) and early vs late.
Median follow-up was 23 months (2–145) and 68 months (2–256) for 4Gy and >4Gy cohorts, respectively. Median dose for the >4Gy cohort was 30Gy (10.5–54Gy). Early and late toxicity incidences were lower in the 4Gy cohort compared to >4Gy across all RT-sites: early toxicity, orbit, 42% v 96%; non-orbital head, 24% v 96%; neck, 22% v 94%; skin, 31% v 87%; late toxicity, orbit, 20% v 71%; non-orbital head, 6% v 66%; neck, 6% v 57%; skin, 0% v 46% (4Gy v >4Gy, respectively). Toxicities among both cohorts were largely low-grade. High-grade early and late toxicities did not occur in the 4Gy cohort. There was 1 high-grade early toxicity (grade 3 dry mouth) and 17 high-grade late toxicities (grade 3 cataracts) in the >4Gy cohort.
RT to HN for iNHL is associated with minimal short- and long-term toxicity and excellent local control among 4Gy and >4Gy treatments. In this setting, “toxicity” concerns should not deter oncologists from potentially curative RT. In select patients where toxicity remains a concern, very low dose 4Gy could be considered.
Keywords: follicular lymphoma, marginal zone lymphoma, low-grade lymphoma, indolent lymphoma, toxicity, head and neck
INTRODUCTION
Lymphoma represents 5–15% of all head and neck cancers.(1, 2) Across all lymphomas, approximately 30% are indolent, non-Hodgkin lymphomas (NHLs).(3) Current National Comprehensive Cancer Network (NCCN) guidelines recommend radiation therapy (RT) in the treatment of indolent lymphomas at doses of 24–30Gy to the involved site.(4) RT provides excellent long-term control and can even be curative for patients presenting with localized disease.(6–10) Complete responses to RT range from 60–80% and 5-year freedom from local progression is approximately 75%.(9, 11–12) RT dose guidelines to head and neck sites follow those of general indolent lymphomas. The recommended dose to nodal and extra-nodal sites of the head and neck is 24–30Gy when using RT as definitive therapy in localized disease.(7, 9, 13–16)
Despite NCCN guidelines, many physicians avoid radiation due to concerns regarding radiation-related toxicities.(17–18) These concerns likely emanate from antiquated practices of treating large volumes with non-conformal techniques, delivering doses in the range of 40 to 50 Gy. While it is important that treatments minimize toxicity as patients with indolent lymphomas have long life expectancies (10, 15, 19–20), many of these fears are unfounded and stem from toxicities associated with the extended fields and larger doses used in the past.(21)
In addition to reducing field and improving techniques (6), in recent years, very low doses of radiation (4Gy), which effectively produce local control in select patients with indolent NHL, have gained popularity.4 Very low dose radiation was initially used only in the palliative setting. Our institution has developed a program utilizing 4Gy in selective potentially curative cases.(22) Complete responses (CR) range from 55–84% (66% in our series), and 3-year in-field freedom from local recurrence reach 92% for those who achieve a CR.(5, 11–12, 23–28) Notably, many studies using this very low dose, but not focusing on head and neck sites, report minimal to no toxicity.(5, 11–12, 23, 25–26, 29–31)
Thus, while RT to involved areas of the head and neck with indolent NHL provides excellent local disease control, it is underutilized due to fear of toxicity. Here, we seek to establish and compare the toxicity profiles of standard versus very low dose radiation to the head and neck in patients with indolent lymphoma.
METHODS
Patient inclusion criteria
Two hundred sixty-six consecutive patients diagnosed between 1986 and 2017 with indolent lymphoma of the head and neck region and treated with involved-site RT using conformal techniques at our institution were included in this retrospective analysis. Indolent lymphomas included marginal zone lymphoma, mucosal associated lymphoid tissue (MALT), follicular lymphoma, cutaneous B-cell lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma. Cases of mixed lymphomas, noted transformation, or a history of diffuse large B-cell lymphoma (DLBCL) in the head and neck were excluded from the analysis. All cases underwent internal pathology review.
Regarding the ethical background of this study, institutional review board approval was obtained, and charts were subsequently reviewed for patient and disease characteristics, treatment data, response to treatment, and toxicity. Patients were staged at initial presentation according to the Ann Arbor staging criteria using PET data when available, and CT, MRI, and clinical evaluation where appropriate.
Toxicity
Toxicity was assessed during RT treatment and subsequent follow-up visits according to the Common Terminology Criteria for Adverse Events version 4 (CTCAEv4). Assessments were performed by the treating radiation oncologist, dedicated lymphoma service nurse within the radiation oncology department, or treating medical oncologist. Toxicities were documented at weekly on treatment radiation visits, the 4–8-week follow-up RT appointment, and subsequent follow-up visits. Toxicity data were extracted from physician notes and/or a standard toxicity form. RT-related toxicities occurring from the start of RT through 2 months post-RT were considered “early”, and those occurring any time later than 2 months after the end of RT were coded as “late”.
The following CTCAEv4 toxicities were grouped into the category “visual changes”: blurred vision, flashing lights, floaters, photophobia, decreased visual acuity, and diplopia. Toxicities were graded 1–4 according to the CTCAEv4. Grade 1–2 were considered low-grade, and 3–4 high-grade. Toxicities were assessed according to site irradiated. RT sites were grouped as orbit, non-orbital head, neck, and skin. Sites treated to the “non-orbital head” included the oral cavity, nasal cavity, salivary glands, sinuses, Waldeyer’s ring, and nodal disease. In the comparison analysis of toxicity incidence between the 4Gy vs >4Gy cohorts, data were stratified by early and late toxicity. Grouped by site treated, early and late toxicities affecting at least 10% of patients in either the 4Gy or >4Gy cohort were considered frequent.
RESULTS
Patient and disease characteristics
Patient and disease characteristics are detailed in Table 1. Two hundred sixty-six patients were analyzed, 62 patients in the 4Gy cohort, and 204 patients in the >4Gy cohort. Median follow-up was 53 months overall (range, 2–256 months), with a shorter follow-up in the 4Gy compared to >4Gy cohort: 23 months in the 4Gy cohort (range: 2–145 months) and 68 months in the >4Gy cohort (range: 2–256 months). The majority of patients had early stage disease at initial diagnosis (63% 4Gy vs 81% >4Gy), and a performance status of 0–1 (98% 4Gy vs 99% >4Gy).
Table 1.
Patient and disease characteristics
| Total cohort (n=266) | 4 Gy (n=62) | >4 Gy (n=204) | |
|---|---|---|---|
| n (%) | n (%) | n (%) | |
|
| |||
| Median age at RT in years (range) | 61 (19–92) | 67 (34–92) | 58 (19–89) |
|
| |||
| Gender | |||
| Male | 140 (52.6) | 31 (50) | 109 (53.4) |
| Female | 126 (47.4) | 31 (50) | 95 (46.6) |
|
| |||
| Race | |||
| Asian | 14 (5.3) | 2 (3.2) | 12 (5.9) |
| Black | 14 (5.3) | 2 (3.2) | 12 (5.9) |
| Hispanic | 1 (0.4) | 0 (0) | 1 (0.5) |
| White | 235 (88.3) | 58 (93.5) | 177 (86.8) |
| Unknown | 2 (0.8) | 0 0 | 2 (1.0) |
|
| |||
| Stage at initial diagnosis | |||
| Early (I, II) | 205 (77.1) | 39 (62.9) | 166 (81.4) |
| Advanced (III, IV, DLBCL) | 61 (22.9) | 23 (37.1) | 38 (18.6) |
|
| |||
| ECOG performance status | |||
| 0–1 | 263 (98.9) | 61 (98.4) | 202 (99.0) |
| 2–3 | 3 (1.1) | 1 (1.6) | 2 (1.0) |
|
| |||
| Histology | |||
| Follicular lymphoma | 117 (44.1) | 28 (45.2) | 89 (43.6) |
| Marginal zone/MALT lymphoma | 110 (41.4) | 21 (33.9 | 89 (43.6) |
| Cutaneous B-cell lymphoma | 22 (8.3) | 10 (16.1) | 12 (5.9) |
| Small lymphocytic lymphoma/ chronic lymphocytic leukemia | 17 (6.4) | 3 (4.8) | 14 (6.9) |
|
| |||
| Smoker | |||
| Yes | 122 (45.9) | 28 (45.2) | 94 (46.1) |
| No | 142 (53.4) | 34 (54.8) | 108 (52.9) |
| Unknown | 2 (0.8) | 0 (0) | 2 (1.0) |
|
| |||
| Relapsed or refractory disease | |||
| Yes | 61 (22.9) | 29 (46.8) | 32 (15.7) |
| No | 205 (77.1) | 33 (53.2) | 172 (84.3) |
|
| |||
| PET SUV | |||
| PET avid | 106 (39.8) | 34 (54.8) | 72 (35.3) |
| non-avid | 10 (3.8) | 2 (3.2) | 8 (3.9) |
| Not done/excluded | 150 (56.4) | 26 (41.9) | 124 (60.8) |
| Median of avid SUV (range) | 7.6 (2.2–38) | 8.55 (2.2–13.5) | 7.5 (2.9–38) |
|
| |||
| Involved site (treated with RT) | |||
| Orbit | 81 (30.5) | 12 (19.4) | 69 (33.8) |
| Oral cavity, larynx, hypopharynx | 25 (9.4) | 7 (11.3) | 18 (8.8) |
| Nasal cavity, paranasal sinuses | 8 (3.0) | 2 (3.2) | 8 (3.9) |
| Thyroid | 13 (4.9) | 0 (0) | 13 (6.4) |
| Salivary glands | 32 (12.0) | 10 (16.1) | 22 (10.8) |
| Cutaneous/subcutaneous | 33 (12.4) | 17 (27.4) | 16 (7.8) |
| Node(s) | 97 (36.5) | 20 (32.3) | 77 (37.7) |
|
| |||
| Median toxicity follow-up from end of RT in months (range) | 53 (2–256) | 23 (2–145) | 68 (2–256) |
Abbreviations: RT, radiation therapy; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; MALT, mucosal associated lymphoid tissue; SUV, standardized uptake value
Treatment characteristics
Treatment characteristics are described in Table 2. The median RT dose in the >4Gy cohort was in accordance with current recommendations at 30Gy (range, 10.5–54Gy) (Supplementary Figure 1). A larger proportion of patients in the 4Gy group compared to the >4Gy group received RT to the non-orbital head (27% vs 25%, respectively) and skin sites (26% vs 7%, respectively), whereas a smaller proportion in the 4Gy group received RT to the orbit (19% vs 34%, respectively) or neck (29% vs 39%, respectively).
Table 2.
Treatment characteristics
| Total cohort (n=266) | 4 Gy (n=62) | >4 Gy (n=204) | |
|---|---|---|---|
| n (%) | n (%) | n (%) | |
|
| |||
| Date of RT | |||
| 1990–1999 | 14 (5.3) | 0 (0) | 14 (6.9) |
| 2000–2009 | 120 (45.1) | 11 (17.7) | 109 (53.4) |
| 2010–2017 | 132 (49.6) | 51 (82.3) | 81 (39.7) |
|
| |||
| Median dose (range) | 24 Gy (4–54) | 4 Gy | 30 Gy (10.5–54) |
|
| |||
| Median delivered fractions (range) | 16 (2–30) | 2 | 17 (7–30) |
|
| |||
| Technique | |||
| IMRT | 87 (32.7) | 15 (24.2) | 72 (35.3) |
| Other‡ | 169 (63.5) | 47 (75.8) | 122 (59.8) |
| Unknown | 10 (3.8) | 0 (0) | 10 (4.9) |
|
| |||
| Field | |||
| Orbit | 81 (30.5) | 12 (19.4) | 69 (33.8) |
| Non-orbital head§ | 68 (25.6) | 17 (27.4) | 51 (25.0) |
| Neck | 98 (36.8) | 18 (29.0) | 80 (39.2) |
| Skin | 31 (11.7) | 16 (25.8) | 15 (7.4) |
|
| |||
| Electrons vs photons | |||
| Electrons | 54 (20.3) | 26 (41.9) | 28 (13.7) |
| Photons | 209 (78.6) | 36 (58.1) | 173 (84.8) |
| Unknown | 6 (2.3) | 0 (0) | 6 (2.9) |
Abbreviations: RT, radiation therapy; IMRT, intensity-modulated radiation therapy
Includes 3D conformal, 2D, electrons
Includes oral cavity, nasal cavity, salivary glands, sinuses, Waldeyer’s ring, and nodal disease
Some patients received RT to multiple sites: 1 patient in the >4Gy cohort was treated to both the orbit and non-orbital head; 1 patient in the >4Gy cohort was treated to the orbit and neck; 10 patients were treated to the non-orbital head and neck (1, 4Gy; 9, >4Gy).
Toxicity
The occurrence of any early toxicity is described in Table 3. Across all sites, there was a higher incidence of early toxicity in the >4Gy compared to the 4Gy cohort: orbit (96% vs 42%), non-orbital head (96% vs 24%), neck (94 vs 22%), and skin (87% vs 31%) (Table 3). Nearly all early toxicities across both RT cohorts were low-grade. There were no early grade 2 toxicities in the 4Gy group, and incidences in the >4Gy group were as follows: orbit, 15%; non-orbital head, 47%; neck, 38%; skin, 20%. High-grade early toxicities were extremely rare and did not occur in the 4Gy cohort. There was one grade 3 early toxicity (dry mouth) in the >4Gy cohort, and no grade 4 early toxicities.
Table 3.
Incidence of patients experiencing any early or late toxicity
| Early toxicity |
Late toxicity |
|||
|---|---|---|---|---|
| Site irradiated | 4 Gy | >4 Gy | 4 Gy | >4 Gy |
| n (%) | n (%) | n (%) | n (%) | |
|
| ||||
| Orbit | (n=12) | (n=69) | (n=10) | (n=68) |
| 5 (41.7) | 66 (95.7) | 2 (20) | 48 (70.6) | |
|
| ||||
| Non-orbital head† | (n=17) | (n=51) | (n=17) | (n=50) |
| 4 (23.5) | 49 (96.1) | 1 (5.9) | 33 (66.0) | |
|
| ||||
| Neck | (n=18) | (n=80) | (n=18) | (n=79) |
| 4 (22.2) | 75 (93.8) | 1 (5.6) | 45 (57.0) | |
|
| ||||
| Skin | (n=16) | (n=15) | (n=15) | (n=13) |
| 5 (31.3) | 13 (86.7) | 0 (0) | 6 (46.2) | |
Includes oral cavity, nasal cavity, salivary glands, sinuses, Waldeyer’s ring, and nodal disease
As with early toxicity, incidence of late toxicity was higher in the >4Gy vs 4Gy cohort across all sites: orbit (71% vs 20%), non-orbital head (66% vs 6%), neck (57% vs 6%), and skin (46% vs 0%), respectively. The majority of late toxicities among both RT cohorts were low-grade. Late grade 2 toxicities were infrequent among both the 4Gy and >4Gy groups: orbit (10% vs 7%), non-orbital head (6% vs 8%), neck (0% vs 11%), and skin (0% vs 0%). There were 17 high-grade toxicities. All high-grade late toxicities occurred in the >4Gy treatment group. Of these high-grade late toxicities, 17 were grade 3 (cataracts requiring surgery) and none were grade 4.
Eight patients were lost to follow-up after their 2 month post-RT visit, and were excluded from the late toxicity analysis. Three of these patients received RT to the orbit, 1 to the non-orbital head, 1 to the neck, and 3 to the skin.
The types of toxicities differed depending on the site treated. Both early and late frequent toxicities are listed in Tables 4 and 5, respectively, according to site treated.
Table 4.
Frequent early toxicities experienced by site of radiation therapy
| Site irradiated | 4 Gy | >4 Gy |
|---|---|---|
| n (%) | n (%) | |
|
| ||
| Orbit | (n=12) | (n=69) |
| Dermatitis | 2 (17) | 40 (58) |
| Xeropthalmia | 3 (25) | 34 (49) |
| Conjunctivitis | 0 (0) | 20 (29) |
| Watering eyes | 0 (0) | 21 (30) |
| Edema | 1 (8) | 20 (29) |
| Pain at site | 0 (0) | 17 (25) |
| Visual changes | 1 (8) | 17 (25) |
| Alopecia | 0 (0) | 7 (10) |
|
| ||
| Non-orbital head † | (n=17) | (n=51) |
| Dermatitis | 0 (0) | 35 (69) |
| Xerostomia | 2 (12) | 34 (67) |
| Dysgeusia | 0 (0) | 31 (61) |
| Mucositis | 0 (0) | 24 (47) |
| Esophagitis | 0 (0) | 17 (33) |
| Pain at site | 0 (0) | 13 (26) |
| Anorexia | 0 (0) | 11 (22) |
| Nausea | 1 (6) | 10 (20) |
| Alopecia | 0 (0) | 9 (18) |
| Dysphagia | 0 (0) | 9 (18) |
| Edema | 0 (0) | 6 (12) |
|
| ||
| Neck | (n=18) | (n=80) |
| Dermatitis | 0 (0) | 58 (73) |
| Xerostomia | 0 (0) | 46 (58) |
| Esophagitis | 0 (0) | 45 (57) |
| Dysphagia | 1 (6) | 35 (44) |
| Hoarseness/ voice changes | 0 (0) | 27 (34) |
| Mucositis | 0 (0) | 26 (33) |
| Dysgeusia | 0 (0) | 14 (18) |
| Alopecia | 0 (0) | 12 (15) |
| Nausea | 1 (6) | 10 (13) |
|
| ||
| Skin | (n=16) | (n=15) |
| Dermatitis | 2 (13) | 11 (73) |
| Alopecia | 2 (13) | 2 (13) |
Includes oral cavity, nasal cavity, salivary glands, sinuses, Waldeyer’s ring, and nodal disease
Table 5.
Frequent late toxicities experienced by site of radiation treatment
| Site irradiated | 4 Gy | >4 Gy |
|---|---|---|
| n (%) | n (%) | |
|
| ||
| Orbit | (n=10) | (n=68) |
| Xerophthalmia | 1 (10) | 28 (41) |
| Cataracts | 0 (0) | 19 (28) |
| Visual changes | 0 (0) | 18 (27) |
| Watering eyes | 0 (0) | 11 (16) |
| Skin changes | 1 (10) | 5 (7) |
| Conjunctivitis | 1 (10) | 3 (4) |
| Dermatitis | 1 (10) | 2 (3) |
| Sinusitis | 1 (10) | 1 (2) |
|
| ||
| Non-orbital head ‡ | (n=17) | (n=50) |
| Xerostomia | 0 (0) | 21 (42) |
| Dysgeusia | 0 (0) | 8 (16) |
|
| ||
| Neck | (n=18) | (n=79) |
| Xerostomia | 0 (0) | 26 (33) |
| Pain at site | 1 (6) | 8 (10) |
|
| ||
| Skin | (n=15) | (n=13) |
| Skin changes | 0 (0) | 6 (46) |
Includes oral cavity, nasal cavity, salivary glands, sinuses, Waldeyer’s ring, and nodal disease
Local Control
Seventy-three percent of patients in the 4Gy cohort, compared to 89% of patient in the >4Gy cohort achieved a CR at the site of RT. There was a total of 13 in-field failures after CR to initial RT, 5 (8%) among the 4Gy cohort, and 8 (4%) among >4Gy. Long term outcome data will be presented in a separate paper.(22)
DISCUSSION
Though recommendations for the treatment of low-grade indolent NHL recommend limited-field low dose RT of 24Gy, radiotherapy is often avoided due to oncologists’ concern of toxicity, particularly in the HN region. While many studies remark on decreased toxicity when lowering RT dose and reducing the field size, until this study, we have not had substantial comparative data on toxicity incidence when using standard low dose versus even further dose reduction to 4Gy therapy in indolent NHL of the HN.(9, 13) Though several studies note common RT-related toxicities, it is usually only the most frequently occurring early and late toxicities that are noted, such as mucositis, dermatitis and other skin changes, xerostomia, or xerophthalmia.(9, 13, 15–16) Our study offers a detailed toxicity profile for both standard low dose and very low dose 4Gy treatment of HN sites (Tables 4 and 5).
Our results show that RT to the HN region in the treatment of indolent NHL is associated with minimal toxicity in the short- and long-term among both 4Gy and >4Gy groups.
Early toxicities were well-tolerated across both cohorts. With the exception of one grade 3 dry mouth in the >4Gy cohort, early toxicities were all low-grade across both treatment groups. Not unexpectedly, there was a lower incidence of early toxicity in the 4Gy cohort than >4Gy across all treatment sites. Importantly, most toxicities experienced by both cohorts resolved before the 2-month follow-up visit.
Late toxicities were likewise well-tolerated across both cohorts. Late toxicity incidence was less than that of early toxicity across all sites and treatment groups. As with early toxicity, late toxicity incidence was, expectedly, higher in the >4Gy cohort than 4Gy. Only 4/59 patients receiving 4Gy experienced any late toxicity. Most were low-grade excepting 17 patients who developed cataracts requiring surgery, all of whom received >4Gy treatment. Per CTCAEv4, cataracts are considered grade 3 if managed with surgical intervention. All of these patients had orbital involvement and local treatment was fully indicated. Of note, no further information regarding whether these were age-related or RT-related cataracts was available. While the dose range for the >4Gy cohort was large (10.5–54Gy), the majority of grade 3 cataracts occurred at doses ≤30Gy (≤ 30Gy, n=15; >30Gy, n=2).
The most common late toxicity for both non-orbital head and neck was xerostomia, which only occurred in the >4Gy cohort: (42% and 33%, respectively) (Table 5). While all incidences of late xerostomia were low-grade and often improved with medication, late xerostomia did not occur with the very low dose. The most common late toxicity among those treated to the orbit was xerophthalmia – all were low-grade and had a lower incidence in the 4Gy group (10% vs 41%, respectively) (Table 5). Xerophthalmia likewise improved with medical intervention.
Studies not limited to the head and neck have found similar incidences of toxicity. Hoskin et al (12) reported high-grade early toxicities were rare and low-grade early toxicities were in line with our findings (24Gy, 57%; 4Gy, 25%). Similarly, Lowry et al9 documented a comparable experience with doses >4Gy, detailing a similar incidence of mucositis (24Gy and 40–45Gy, 25%) and pooled skin reactions (erythema, dry and moist desquamation: 24Gy, 48%; 40–45Gy, 74%). In a retrospective review of 40 patients with indolent NHL limited to the HN treated with RT, surgery, and/or chemotherapy, MacDermed et al (13) also noted a high occurrence of RT-related mucositis and dermatitis, though incidence was unquantified.
Hoskin et al (12) report late toxicity rates of 37% among the 24Gy cohort and 23% for 4Gy. Our >4Gy experience had a notably higher rate, potentially attributable to the wide dose range in our cohort as well as our investigation of solely HN sites that include sensitive structures where an alteration in function might be more noticeable to patients. While the incidence of late toxicities reported by Lowry et al (9) appear lower compared to our experience, this is likely accounted for by lack of stratification by site treated and reporting of specific toxicities rather than a pooled incidence of any late toxicity.
Regarding orbital toxicity, several retrospective studies have reviewed toxicity associated with 4Gy and 24Gy treating indolent NHL involving the orbital adnexa. Goda et al (16) report their single-institution experience of 89 patients with ocular adnexal involvement managed with primary RT (25–30Gy). Acute toxicities include periorbital erythema, conjunctival injection, and excessive tearing or swelling, all noted as “mild.” As in our series, acute toxicities were largely self-limiting. Late toxicity occurred in 45% of patients, with the most common being cataract formation (median time to formation, 3.6 years). Incidence of grade 3 cataract was reduced with lens shielding (7-year rate of 15% with shielding vs. 41% without). Among patients undergoing cataract removal, vision was restored.
MD Anderson’s experience of 22 patients with ocular adnexal indolent NHL treated with 4Gy showed minimal acute toxicity – 1 dry eye.34 Our data reflect a higher incidence, possibly due to differing timepoints of data collection. Pinnix et al (34) collected toxicity data at 2- and 4-month timepoints whereas our study included data from start of RT through 2-months post-RT. A review of Stanford’s experience treating 27 ocular adnexal sites with 4Gy also showed mild acute side effects including dry eye, conjunctivitis resolving with corticosteroids, and transient periorbital edema resolving without intervention.(35) With a median follow up of 26 months, there were no RT-related late toxicities. Lens shielding was used as deemed appropriate. One patient developed bilateral cataracts felt unlikely related to RT due to significant additional risk factors. While late toxicity data of 4Gy show promising results, continued follow up will be important to assess for cataract development.
The overwhelmingly low-grade early and late toxicities of both 4Gy and >4Gy treatments reflect an acceptable radiation toxicity profile. Low-grade toxicities are considered tolerable – a significant outcome in such a sensitive site as the HN. Moreover, resolution by the 2 month follow-up of early toxicities is encouraging. Our data are encouraging, finding few severe late effects. High-grade late effects occurred solely among patients receiving >4Gy.
Given the prolonged disease course and lengthy survival of patients, it is important that disease control be associated with as minimal treatment-related toxicity as possible. Our data provide highly specific HN toxicity data across multiple HN sites for both standard dose and very low dose RT. We have found that both 4Gy and >4Gy treatments achieve durable responses and are associated with mild short and long-term toxicity profiles in the HN. While current guidelines recommend 24Gy in the treatment of indolent NHLs, which our data suggest is extremely well tolerated, in cases where patients are unable to tolerate the full dose or where there is increased concern over HN toxicity, 4Gy is a reasonable option.
We recognize that the small sample size of the 4Gy treatment group, made smaller when stratified by site treated, makes for a more limited toxicity analysis. The wide range of follow up may also impact late toxicity data. However, late toxicities largely presented early in follow up and either resolved with time or remained a chronic issue. Standardization of follow-up toxicity data was not possible given the retrospective nature of the study but is a worthwhile endeavor for future prospective studies. The dose range for the >4Gy cohort was large (10.5–54Gy) raising the question whether more of the toxicity in this cohort could be attributable to doses above the upper limit of the standard dose. However, the number of patients receiving these higher doses was limited (20 patients received >36Gy.)
CONCLUSIONS
As expected, when RT dose increases, some toxicity incidence rises. Yet, even at higher doses, toxicities are well-tolerated with nearly all Grade 1–2. Overall, RT should not be avoided in the HN region due to fear of toxicity as 24Gy is very well tolerated. However, in reliable patients who require larger fields, and for whom RT-related toxicity is a concern, it is reasonable to consider 4Gy with close follow up.
Supplementary Material
Supplementary Figure 1. Dose distribution of patients receiving >4 Gy
Acknowledgments and Funding
This work was supported by the Lymphoma Foundation, the Connecticut Cancer Foundation, the National Cancer Institute (P30 CA008748 to J.Y.), and the American Society of Hematology HONORS award. The funding sources had no involvement in the design of the study, collection, analysis, and interpretation of data and in writing the manuscript.
Footnotes
Authorship
Monica Chelius made contributions to the conception and design of the work; the acquisition, analysis, and interpretation of data; and the drafting and revision of the work for important intellectual content. Karen Chau made contributions to the acquisition and analysis of data; the revision of the work for important intellectual content. Joanna Yang made contributions to the conception and design of the work; the analysis and interpretation of data; and the revision of the work for important intellectual content. Joachim Yahalom made contributions to the conception and design of the work; the analysis and interpretation of data; and the revision of the work for important intellectual content. All authors have approved the final version of this work and agree to be accountable for all aspects of the work.
Conflicts of interest: The authors have no conflicts of interest to disclose.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Reference List
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Figure 1. Dose distribution of patients receiving >4 Gy
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.