Summary
Background
Given the favorable prognosis of patients with gastric mucosa-associated lymphoid tissue lymphoma, treatment-related toxicity should be minimized. We aimed to evaluate the efficacy of 4 Gy radiation therapy (RT) given in a response-adapted approach.
Methods
We conducted a single-center, single-arm prospective trial at MD Anderson Cancer Center (Houston, TX, USA) of response-adapted ultra-low-dose RT for patients with newly diagnosed or relapsed stage I–IV H. pylori–negative gastric MALT lymphoma (NCT03680586). Patients received external beam photon-based RT for a total dose of 4 Gy in two fractions. Patients with complete response (CR) to 4 Gy via endoscopy and imaging at 3–4 months were observed; patients with partial response were re-evaluated in 6–9 months. Residual disease at 9–13 months or stable or progressive disease at any time required an additional 20 Gy. The primary endpoint evaluated the efficacy of ultra-low-dose 4-Gy gastric radiation, measured as gastric CR at 1 year (second evaluation timepoint) after 4-Gy treatment. All analyses were performed as intention to treat. The trial is currently completed and closed to enrollment.
Findings
We enrolled 24 eligible patients from March 27, 2019 through October 12, 2021; median age was 67 years (range 40–85); 20 (83%) had stage I disease, 1 (4%) stage II, and 3 (13%) stage IV. Median follow-up time was 36 months (IQR 26–42). Twenty patients (83%) experienced CR to 4 Gy (16 at 3–4 months, 4 at 9–13 months); 2 patients received 20 Gy for symptomatic stable disease at 3–4 months and 2 for residual disease at 9–13 months; all experienced a CR. The 3-year local control rate was 96%, with one local relapse at 14 months after 4 Gy RT salvaged successfully with 20 Gy. One patient with stage IV disease experienced distant relapse. No grade ≥3 adverse events were noted including no treatment-related deaths.
Interpretation
Most patients experienced CR after 4 Gy RT; all who required an additional 20 Gy experienced CR. This response-adapted strategy could be used to select patients who would benefit from additional RT and spare others potential associated toxicity.
Funding
National Cancer Institute Cancer Center Support (Core) Grant P30 CA016672
Introduction
Evolving treatment paradigms for many lymphoma diagnoses attempt to maintain excellent outcomes while reducing the treatment-related toxicity burden. For patients with marginal zone lymphoma (MZL) involving the stomach (extranodal marginal zone lymphoma of mucosa-associated lymphoid tissues, or MALT lymphoma), previous treatments have included radical surgery such as gastrectomy, multi-agent chemotherapy, or extended-field high-dose radiation therapy (RT). More recently, therapy for patients with early-stage disease has involved a moderate RT approach with doses of 24–30 Gy.1–4 Although this treatment carries a relatively low risk of significant long-term morbidity, attempts have been made to omit RT by first giving antibiotic therapy to patients with, or even those without, identified driver infections (e.g., H. pylori [HP]).5,6
From an RT perspective, the focus on treatment de-escalation has led to smaller involved-site RT fields and incorporation of advanced treatment techniques to facilitate the reduction of normal-tissue doses.7–9 Prospective trials10,11 and retrospective analyses12–16 have reported on the efficacy of lower prescription RT doses such as 4 Gy for low-grade lymphoma. The FORT trial, which included patients with follicular or MZL, verified 24 Gy (vs 4 Gy) as the optimal RT dose for durable local control (LC) of indolent lymphoma. However, results for the MZL subpopulation were more promising, with 5-year local progression-free rates of 88% for 4 Gy vs 100% for 24 Gy. A response-adapted approach to treatment, starting with 4 Gy and giving additional dose only if necessary, was first validated in patients with orbital indolent B cell lymphoma;11 encouraging LC and freedom from distant relapse rates were confirmed.
For these reasons, we explored a novel response-adapted approach to RT for patients with HP-negative stage I-IV gastric MALT lymphoma: we conducted a single-arm prospective trial in which patients received initial therapy consisting of 4 Gy in 2 fractions; only those patients with an incomplete response were given an additional 20 Gy for completion of therapy. We hypothesized that this approach would spare most patients the need for additional RT and the corresponding risk of potential added toxicity.
Methods
We performed a single-arm prospective trial (full protocol, appendix page 3) of ultra-low-dose RT in patients (age ≥18 years) with newly diagnosed or relapsed stage I-IV HP-negative gastric MALT lymphoma (registered with ClinicalTrials.gov: NCT03680586). This protocol was IRB-approved by MD Anderson Cancer Center. All study participants gave written informed consent. Shortly after activation, biomarker correlative studies were made optional. The second response assessment timepoint was changed to 6–9 months to allow for greater flexibility. Complete inclusion/exclusion criteria are available in the full protocol (appendix page 3). (appendix page 3). Patients with residual biopsy-proven lymphoma after HP eradication or systemic therapy were eligible. Negative HP testing within 6 months was required. Systemic therapy and/or antibiotic therapy were allowed if indicated. Patients with autoimmune disease (except scleroderma) were eligible. Prior RT was allowed if re-treatment could be delivered safely. Patients with bulky tumors (defined as >10 cm in any dimension) were ineligible. Given the expected low toxicity profile of treatment, performance status was not an exclusion criteria. As RT is a known teratogen, pregnant patients were excluded and pregnancy testing within 2 weeks of protocol entry was required.
Before enrollment, patients were required to undergo a complete history and physical examination to determine ability to tolerate treatment procedures, laboratory studies including kidney/liver function to establish baseline and allow for monitoring post-treatment, and a comprehensive examination by a gastrointestinal specialist to document endoscopy findings. Required radiographic studies included at minimum computed tomography (CT) (preferably contrast-enhanced), and fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) or magnetic resonance imaging (MRI) were recommended. Bone marrow biopsy was obtained at the discretion of the medical oncologist. All patients with sufficient material were tested for t(11;18).
Procedures
Patients were to receive external beam photon-based RT for a total dose of 4 Gy in two fractions. Treatment simulations and delivery were done while the patients had an empty stomach and performed deep-inspiration breath hold.8,9 RT volumes were defined as follows. The clinical target volume (CTV) encompassed the entire stomach plus lymph nodes and/or proximal duodenum if suspected of disease involvement. For the initial 4 Gy, 3D conformal radiation therapy was used. The planning target volume (PTV) was created by expanding the internal CTV (iCTV; entire stomach CTV accounting for internal motion, as assessed on multiple breath-hold images) by 1–2 cm. Patients requiring an additional 20 Gy received intensity-modulated RT. For this treatment, the PTV was created by expanding the iCTV by 5–15 mm. Daily CT-based image guidance was used for all treatments.
Response was assessed by endoscopy and imaging 3–4 months after treatment at our institution; one patient had follow up and 20 Gy treatment guided by the protocol team at a local facility. Complete response (CR) was defined as no evidence of disease on biopsies obtained via endoscopy. Twelve to sixteen biopsies evaluating the entire stomach were recommended; this included biopsies from the gastric antrum (n=4) and different regions of the body (n=8) for patients without concerning visualized abnormalities. Focal findings were evaluated with additional directed biopsies. For patients with a clinical or radiographic mass, complete mass resolution was also confirmed. In patients with FDG-avid disease before treatment, CR was defined as a Deauville score of 1, 2 or 3, according to the Lugano classification.17 Partial response (PR) was defined as a decrease in gastric clinical disease burden ±radiographic examination by ≥50% by sum of the disease diameters or a 50% decrease in the number of involved biopsies (±2 biopsies for sampling error). Minimal response (MR) was defined as a response less than PR but greater than stable disease (SD); SD and progressive disease (PD) were defined as no change or an increase, respectively, in gastric disease by clinical, radiographic, or microscopic examination.
Patients with a CR at the first follow-up (at 3–4 months) were observed, with subsequent evaluations at the discretion of the multidisciplinary team. Patients with SD or PD at 3–4 months were recommended treatment with an additional 20 Gy. Patients with an initial MR or PR were re-evaluated with imaging and endoscopy again in 6–9 months. If CR was experienced, the patients were observed; otherwise an additional 20 Gy was recommended (treatment schema, appendix p 1).
Statistical analyses and end points
This protocol was designed as a pilot study without a tested hypothesis, power calculation, or formal sample size determination. There were no planned interim or sensitivity analyses. The primary endpoint of the study was the efficacy of ultra-low-dose 4-Gy gastric radiation, measured as gastric CR at 1 year (second evaluation timepoint) after 4-Gy treatment; we also reported LC after the entire response-adapted therapy program (post-hoc analysis). Secondary endpoints included evaluation of distant recurrence (less relevant for advanced stage patients) at one year and toxicity associated with gastric RT. Exploratory endpoints (reported separately) assessed the feasibility of RT response prediction using patient biomarkers. Patients declining endoscopy-based reassessment would be deemed not assessable. Patients declining the recommended therapy would be counted as failures of the primary endpoint. All 24 patients were assessed for primary and secondary outcomes and for safety with intention to treat.
Patient demographics, disease characteristics, and clinical outcomes were reported with descriptive statistics. Fisher’s exact test was used to evaluate the associations between categorical variables. Disease recurrence endpoints were defined from RT start date and censored at the time of last clinical follow-up. Persistent disease at 1 year (second evaluation timepoint) or required treatment with an additional 20 Gy earlier than 1 year for SD/PD were considered primary endpoint events (gastric CR at 1 year). The 95% confidence interval of gastric CR at 1 year was estimated using the binomial exact method. For LC, we considered any local failure after completion of the entire response-adapted program (4 Gy or 4 Gy then 20 Gy) as an event. Distant recurrence events included development of new disease outside the RT field. Time-to-event analyses, including local control and freedom from distant recurrence rates, were estimated using Kaplan-Meier method, with their 95% confidence intervals. Median follow-up times with 95% confidence intervals were calculated by using the reverse Kaplan-Meier method.18 All statistical analyses were done with SAS 9.4 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA).
Gastrointestinal toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03: June 14, 2010). If patients had symptoms at baseline that persisted after therapy, those symptoms were considered a form of toxicity (e.g., a patient with baseline mild nausea that persisted after treatment was counted as having grade 1 nausea in the toxicity assessment). Patient reported quality of life outcomes were not collected.
Role of the funding source
JRG, WD, and CCP had access to the raw data. The funder of the study had no role in study design, data collection, data interpretation, or writing of the report.
Results
We enrolled 24 patients meeting inclusion criteria from March 27, 2019 through October 12, 2021 (Figure 1). Screened patients (n=34) were excluded or removed from protocol for bulky disease (n=2) or HP-positive disease (n=1). Other patients meeting criteria did not enroll due to: refusal of full study participation (n=5), protocol RT deemed unnecessary due to planned systemic therapy (n=1) and stage IV disease (n=1). Patient and disease characteristics are reported in Table 1. Median age was 67 years (range 40–85) and 15 of 24 patients (63%) were female sex. Twenty-one of 24 patients (87%) had stage I-II disease. Of 15 tested patient biopsy specimens, 4 were positive for t(11;18). Most patients (n=21) had pretreatment FDG PET-CT imaging. Six patients had FDG-avid disease noted on PET-CT, and 5 had evidence of stomach thickening on CT (evaluated on CT or CT portion of PET-CT). Eight patients had prior treatment, 2 of 24 (8%) with systemic therapy and 6 of 24 (26%) with antibiotics for HP-positive (3 of 24, 13%) or HP-negative (3 of 24, 13%) disease. All 3 patients with HP-positive disease at diagnosis were treated with HP eradiation antibiotic therapy: one experienced residual lymphoma after 18 months (PR), one had SD at 11 months, and one had disease relapse 8 months after the original diagnosis.
Figure 1.
CONSORT diagram with number of patients screened, enrolled, and treated with completed follow up per protocol.
Table 1.
Patient and disease characteristics
| Characteristics | Value or No. of Patients (%) (n=24) |
|---|---|
| Patient | |
| Age, years, median (range); (interquartile range) | 67 (40–85); (58–74) |
| Female sex | 15 (63) |
| Race | |
| Asian | 4 (17) |
| Black | 0 (0) |
| Hispanic | 2 (8) |
| White | 18 (75) |
| Autoimmune disease | 1 (4) |
| B symptoms | 1 (4) |
| GI symptoms before treatment | 18 (75) |
| Ever positive for H. pylori | 6 (25) |
| Disease | |
| H. pylori initially positive at lymphoma diagnosis | 3 (13) |
| H. pylori confirmatory test performed (n=17, 71%) | |
| Blood | 3 (13) |
| Stool | 8 (33) |
| Breath | 5 (21) |
| Blood and breath | 1 (4) |
| Not tested | 7 (29) |
| t(11;18) (n=15 tested) | |
| Positive | 4 (17) |
| Negative | 11 (46) |
| Not tested | 9 (37) |
| Disease location | |
| Stomach | 21 (87) |
| Stomach and duodenum | 3 (13) |
| Disease stage at initial diagnosis | |
| I | 20 (83) |
| II | 1 (4) |
| III | 0 (0) |
| IV | 3 (13) |
| Bone marrow status (n=18) | |
| Negative | 17 (71) |
| Positive | 1 (4) |
| Not tested | 6 (25) |
| Images obtained before treatment | |
| PET-CT | 21 (88) |
| MRI | 1 (4) |
| CT | 2 (8) |
| PET-CT-avid disease (n=21) | |
| Yes | 6 (29) |
| Stomach thickening on CT | 5 (21) |
| Prior Therapy | |
| Systemic therapy | 2 (8) |
| Antibiotics (H. pylori-positive) | 3 (13) |
| Antibiotics (H. pylori-negative) | 3 (13) |
| None | 16 (67) |
Abbreviations: GI, gastrointestinal; PET, positron emission tomography; MRI, magnetic resonance imaging; CT, computed tomography
Median follow-up time for the entire cohort was 36 months (interquartile range 26–42). Sixteen patients had a CR at first evaluation (3–4 months) after 4 Gy, and an additional 4 patients had disease conversion to CR at second evaluation (9–13 months); the median time to CR for these 20 patients was 4 months (range 3–12). Therefore, the primary endpoint of complete gastric response at 1 year with 4 Gy treatment was 83% (95% CI 63%–95%). All six patients with FDG-avid disease had resolution of imaging findings concordant with pathologic CR.
Four patients (3 male, 1 female) received an additional 20 Gy with intensity-modulated RT for SD/PD at 3–4 months (2 patients) or residual disease after 4 Gy at 10 and 13 months (2 patients) according to the response-adapted protocol. All experienced a CR after response-adapted therapy. Characteristics of these patients are reported in Table 2 (appendix p 2). The median time to response among these 4 patients was 9 months (range 4–12); two of these four patients had disease noted on the first evaluation after 20 Gy.
Among all 24 patients, the 3-year LC rate after the response-adapted protocol was 96% (95% CI 88%–100%, Figure 2), with one female patient who experienced a CR after 4 Gy developing relapsed disease in the stomach at 14 months. This patient was treated with 20 Gy and again experienced a CR. All 24 patients (100%) were in CR at last follow-up after 4 Gy (19 patients) or 24 Gy (5 patients: 4 per protocol, 1 for relapse). Each patient’s response to initial 4 Gy treatment and additional 20 Gy treatment (if applicable) is represented in Figure 3. One patient with stage IV disease experienced distant relapse with diffuse large B-cell lymphoma at 14 months and is in CR after systemic therapy; a complete gastric response to 4 Gy RT was confirmed prior to the distant relapse. Therefore, the secondary endpoint of freedom from distant relapse rate was found to be 100% at 1 year (95% CI 100%–100%) and 96% (95% CI 88%–100%) at 3 years. No additional patients received systemic therapy after RT.
Figure 2.
(A) Local control and (B) freedom from distant relapse rates after completion of the entire response-adapted protocol therapy
Figure 3.
Swimmer plot displaying time to complete response with initial 4 Gy treatment, time to complete response with additional 20 Gy (if applicable), and relapse events. Each bar represents an individual patient.
Among the 15 patients with known t(11:18) status, 2 of the 4 patients (50%) with positive t(11;18) status required an additional 20 Gy of RT (either per protocol or for relapse) compared with 3 of 11 patients (27%) without the translocation (P=0.56). In our cohort, 4 of 8 patients previously treated with systemic or antibiotic therapy required an additional 20 Gy, compared to 1 of the 16 untreated patients (p=0.13). All three patients with previously HP-positive disease refractory to antibiotics experienced CR after only 4 Gy.
Eighteen patients of 24 total (75%) had gastrointestinal-related symptoms before treatment. After treatment, symptoms improved in 11 of those 18 patients and resolved in the other 7 patients. We assessed the secondary endpoint of toxicity associated with gastric RT during and after treatment. Toxicities with 4 Gy and 20 Gy are reported in Table 3. The two patients with grade 2 abdominal pain had pain before RT which persisted after treatment, relatively unchanged. No grade 3 or higher toxicities were reported. At last follow up, no patients experienced renal dysfunction beyond baseline deficits that were present prior to treatment. Patient reported outcomes including quality of life data were not collected.
Table 3.
Adverse events with 4 Gy and 20 Gy radiation
| Adverse event | 4 Gy (Number of patients) | 20 Gy (Number of patients) |
|---|---|---|
| Fatigue | ||
| Grade 1 | 1 | 0 |
| Grade 2 | 0 | 0 |
| Grade 3 | 0 | 0 |
| Grade 4 | 0 | 0 |
| Grade 5 | 0 | 0 |
| Diarrhea | ||
| Grade 1 | 1 | 0 |
| Grade 2 | 0 | 0 |
| Grade 3 | 0 | 0 |
| Grade 4 | 0 | 0 |
| Grade 5 | 0 | 0 |
| Nausea | ||
| Grade 1 | 9 | 3 |
| Grade 2 | 1 | 0 |
| Grade 3 | 0 | 0 |
| Grade 4 | 0 | 0 |
| Grade 5 | 0 | 0 |
| Vomiting | ||
| Grade 1 | 2 | 0 |
| Grade 2 | 0 | 0 |
| Grade 3 | 0 | 0 |
| Grade 4 | 0 | 0 |
| Grade 5 | 0 | 0 |
| Pain | ||
| Grade 1 | 5 | 0 |
| Grade 2 | 2 | 1 |
| Grade 3 | 0 | 0 |
| Grade 4 | 0 | 0 |
| Grade 5 | 0 | 0 |
Discussion
In this study, we evaluated the efficacy of a response-adapted approach to definitive RT for patients with gastric MALT lymphoma. We found that 83% of patients experienced a CR to the initial dose of 4 Gy. For patients who required another 20 Gy, all experienced CR if given sufficient time to respond. Treatment was well tolerated, with no grade 3 or higher toxicity observed.
Outcomes after standard-dose RT for gastric MALT are excellent, a, with LC rates of >90% in most studies. Others evaluating doses slightly lower than 30 Gy1,3,19 have not found any detriment to reducing the dose. Prior prospective trials10,11 and retrospective analyses12–16 have assessed the efficacy of 4-Gy RT for low-grade lymphomas. The multi-institutional FORT trial reported 5-year local progression-free rates of ~70% for 4 Gy vs ~90% for 24 Gy RT.11 Because of these results, many consider 4 Gy RT to be inappropriate for definitive-intent therapy for patients with early-stage disease. However, outcomes for the subpopulation of patients with MZL were compelling, with 5-year LCrates of 88% for 4 Gy (vs 100% for 24 Gy). The authors noted differences in the natural history of MZL and also acknowledged that the apparent superiority of 24 Gy for the MZL cohort was not definitive.
Concern also exists regarding possible increased distant relapse risk if patients with early-stage disease are treated with only 4 Gy. However, even higher RT doses do not completely prevent distant relapse. Older studies of patients with early-stage MALT treated with definitive RT (most ≥30 Gy) reported relapses, mostly distant, in 24% of patients.20 In a single institutional series of patients receiving 4 Gy for follicular lymphoma or MZL12 the overall response rate was 90% for all treated sites, with 68% of patients experiencing CR. Patients with potentially curable lesions did not have inferior outcomes. In a response-adapted trial of patients with orbital indolent B cell lymphoma treated with an initial 4 Gy, the freedom from distant relapse rate was 95% at 2 years for patients with stage I disease.11 Given the promising results with low-dose 4-Gy RT, it seems reasonable to offer a response-adapted approach to select out these favorable responders and spare others unnecessary toxicity.
This shorter initial treatment schedule has numerous advantages. Having fewer treatment days minimizes nausea, the most common acute toxicity associated with stomach-directed RT, and also reduces costs related to medical bills, time off work, and travel. There is also the potential for decreased late treatment-related toxicity with lower RT doses. RT fields have evolved from extended-field (covering the entire peritoneal cavity) to drastically reduced involved-site RT covering the stomach and involved adjacent nodes;21 however, even with these smaller fields, stomach-directed RT plans often result in treatment of the inferior heart, including the left ventricle,22 with known long-term negative effects. Abdominal organs are also at risk of RT-induced toxicity. Lee and colleagues evaluated patients who received RT for gastric MALT (median dose 30 Gy) and found a 9.6% 5-year cumulative risk of diabetes mellitus development, significantly higher than patients who did not receive RT (1.6%) (P=0.008).23 The mean pancreas dose was independently associated with diabetes mellitus development risk.23 Increased RT spleen dose is associated with late infection-related mortality and lymphopenia.24 Finally, both the liver and kidneys are at risk of dysfunction after excess RT exposure.25 Depending on patient age at treatment, secondary malignancies can also be a concern. For patients with gastric MALT lymphoma, an increased risk of gastric adenocarcinoma, as much as 6–10 times higher than the general population, has been reported.26 Hence, these patients are recommended to have thorough evaluations for precancerous lesions (e.g. intestinal metaplasia, dysplasia) at initial and follow-up endoscopy.26 Prior RT is a known risk factor for dose-dependent development of gastric adenocarcinoma27; use of ultra-low-dose RT could mitigate this risk.8
Many practitioners attempt to spare patients the toxicity of RT by avoiding this treatment modality entirely. Systemic therapies such as combination chemotherapy or single-agent rituximab are not preferred for patients with early-stage disease due to excess toxicity and inferior LC rates, respectively.28 It is appropriate to attempt RT-avoidance for patients with concurrent HP infection (without chromosomal translocation t(11;18)), because the rates of CR with antibiotic therapy alone can be as high as 50%−90%.29 Even for patients without HP infection, antibiotic therapy can result in complete response rates as high as 57%.6,30 However, a CR to antibiotic regimens can take longer to manifest, and the National Comprehensive Cancer Network guidelines recommend waiting up to 18 months if possible. Some practitioners argue that 4 Gy of RT, with slightly inferior LC rates, should not be offered as curative-intent therapy for patients with early-stage disease. Nevertheless, national and international guidelines recommend antibiotic therapy and lengthy observation periods, even in the setting of residual active disease, for this same population with early-stage disease.
In the current study, we observed the same delayed disease regression patterns as those observed with antibiotic therapy. Four patients required continued observation until the second follow-up evaluation before a CR was documented with 4 Gy. If patients have no significant symptoms, they should be encouraged to wait before receiving potentially unnecessary additional therapy. Interestingly, higher dose RT does not necessarily guarantee a faster CR; 2 of the 4 patients requiring an additional 20 Gy per protocol were not in CR at first response assessment after receiving 20 Gy but converted to CR with additional time.
Another caution relates to the importance of a thorough endoscopic evaluation after therapy, because gastric MALT commonly has subtle clinical findings and often lacks radiographic abnormalities. Patients should have evaluation of the entirety of the stomach, with blind biopsies even in normal-appearing areas within the stomach antrum and body. In our study, the patient who experienced local relapse after an initial CR to 4 Gy had a very subtle flat scar that was not biopsied at time of documented CR; this was the location of positive biopsy at relapse. It is possible that residual disease may have been missed at the first response evaluation.
Given the treatment de-escalation involved in this protocol, it is important to consider which patients may be most appropriate for a response-adapted approach. We excluded patients with bulky disease, and we did not encounter any patients with a large cell component or with active, bleeding ulcers. Whether this strategy is appropriate for such patients is still being determined. However, patients refractory to prior systemic and antibiotic therapy were included. Interestingly, all 3 patients with HP-associated disease at diagnosis that was refractory to antibiotic therapy experienced CR to 4 Gy RT. Although other studies have reported that prior therapy is associated with improved outcomes after RT,31 we found that a higher percentage of pre-treated patients with refractory disease required an additional 20 Gy compared to untreated patients. In this study, fewer patients had disease with t(11;18) compared to other studies of HP negative patients32; however, some patients were previously HP positive and not all patients were tested due to limited material. Although disease with a positive t(11;18) is unlikely to respond to antibiotic therapy alone, the presence of this translocation did not necessarily confer resistance to lower RT doses: of the 4 patients with a positive MALT1 t(11;18) translocation, 2 responded completely to the initial 4 Gy. Patients with t(11:18) should be watched more closely than others given the knowledge we have on antibiotic treatment resistance in this population. Some patients may experience increased anxiety over the potential need for another round of treatment; although we have found that adequate patient counseling can alleviate some of this anxiety, a response-adapted approach may not be ideal for some patients.
The main limitations of our study include limited follow-up and small patient numbers. For patients with gastric MALT lymphoma, lifelong follow up is recommended to identify late recurrences,33–35 and additional observation will hopefully confirm the durability of the excellent outcomes that we observed. With only 24 patients included, the applicability of our conclusions to a broader patient population is limited. Additional larger studies, perhaps powered for non-inferiority, are needed to confirm the efficacy of this response-adapted approach to treatment.
In conclusion, through this prospective study of patients with HP-negative gastric MALT lymphoma, we documented excellent outcomes after a response-adapted approach, with most patients experiencing the primary endpoint, a complete gastric response at 12 months after receipt of just 4 Gy. After the response-adapted program, only one relapse was noted, and that was successfully salvaged with a higher dose of radiation. As expected, treatment was well tolerated. This strategy could be considered as a means of identifying patients who would benefit from longer RT courses while sparing others from unnecessary treatment-related toxicity. Additional follow-up is required to confirm long-term excellent outcomes with response-adapted ultra-low-dose treatment.
Supplementary Material
Research in Context.
Evidence before this study
A thorough literature review was initially conducted on January 17, 2018 before designing this prospective trial. We reviewed all pertinent publications indexed in PubMed and identified from Google Scholar from 1998 to 2018 identified with the search terms “radiation therapy”, “radiotherapy”, “marginal zone lymphoma”, “gastric MALT”, “extranodal marginal zone lymphoma”, and “mucosa-associated lymphoid tissue”. Given the rarity of this diagnosis, all publications including retrospective works were included.
Added value of this study
There are numerous retrospective and prospective reports of the encouraging results with ultra low dose RT (i.e. 4 Gy); however, when compared to standard dose therapy, 4 Gy remains slightly inferior in terms of local control. For this reason, practitioners hesitate to use this dose for definitive therapy in early stage patients. To our knowledge, this is the first report of a prospective trial utilizing response-adapted radiation therapy to dramatically decrease the dose of radiation therapy given to patients with gastric MALT lymphoma, while still providing a mechanism to ensure that patients requiring higher dose are adequately treated. This study provides evidence that a response-adapted approach starting with only 4 Gy is safe and effective, resulting in outcomes comparable to those of standard dose therapy while sparing ~80% of patients the possible toxicities of standard dose therapy.
Implications of all the available evidence
Our study adds to the body of existing evidence for the efficacy of 4 Gy in the treatment of marginal zone lymphoma, with a greater proportion of patients experiencing complete response in this study than in some of the older studies due to the planned ability to give additional dose if necessary. This study is limited by small numbers and lack of long term follow up. For patients with higher risk of toxicity from radiation therapy or when observation alone is considered for any reason, this approach provides a non-toxic and effective alternative. An ongoing study (NCT05929612) evaluates this approach in other marginal zone lymphoma disease sites with a larger patient cohort.
Acknowledgements
Christine Wogan, Manager of Technical Writing and Publications at MD Anderson Cancer Center, provided editorial assistance to the authors during preparation of this manuscript.
Funding
Supported in part by National Institutes of Health (NIH), National Cancer Institute Cancer Center Support (Core) Grant P30 CA016672 to The University of Texas MD Anderson Cancer Center (PI: PW Pisters). Suport for the biomarker work associated with this protocol (reported separately) was generously provided by the Division of Radiation Oncology Biomarker Strategic Initiative and the Sterling Foundation.
Footnotes
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Declarations of interests
Dr. Pinnix has research support from Merck. Otherwise, none of the authors report any relevant conflict of interest.
Data Sharing Agreement
Deidentified individual participant data that form the basis for the reported results will be made available 3 months after publication for a period of 5 years after the publication data after initiation and execution of a materials transfer agreement between MD Anderson Cancer center and the party requesting the data.
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Data Availability Statement
Deidentified individual participant data that form the basis for the reported results will be made available 3 months after publication for a period of 5 years after the publication data after initiation and execution of a materials transfer agreement between MD Anderson Cancer center and the party requesting the data.